Phthalimide carboxylic acid derivatives

ABSTRACT

The present invention relates to phthalimide carboxylic acid derivatives of formula (I), methods for their preparation, pharmaceutical compositions containing them and their use in medicine, specifically in the treatment of cancer. (I), wherein X is O or S; R 1  is a phthalimide carboxylic acid group of formula (II). R is hydrogen, C 1 -C 6  alkyl, aryl or C 1 -C 3  alkylaryl and R 2 , R 3  and R 4  represent various substituents.

The present invention relates to novel compounds useful as inhibitors ofheparanase. The invention also relates to methods for their synthesis,pharmaceutical compositions comprising the novel compounds and their usein medicine, in particular for the treatment of cancer.

Heparanases are enzymes that can degrade heparan sulfate, heparin andheparan sulfate proteoglycans and hence function as importantcarbohydrate degrading enzymes.

The extracellular matrix (ECM), which is comprised largely ofcarbohydrates, is the structural surround for cells in a multicellularorganism and acts as a key modulator and mediator of their physiology,differentiation, organisation and repair. It also acts as the principalbarrier to tumour growth and metastasis. Hence, tumour cells secrete anumber of degradative enzymes, including heparanases, in order tobreakdown the ECM so that there is ample space to traverse. Degradationof the ECM is also required to provide avenues for new blood vesselformation (angiogenesis). Tumours promote abnormal angiogenesis in orderto supply the increased nutrient requirements of rapidly growing tumors.

Studies have demonstrated that inhibiting even just one ECM degradingenzyme appears to provide significant benefit in treating cancer. Forexample, inhibitors of certain proteases have been studied inpreclinical and clinical trials as anticancer agents (Fang J et al.,(2000) Proc. Natl. Acad. Sci. USA, April 11, 97(8), 3884-9 & KondragantiS et al., (2000) Cancer Res, December 15, 60(24), 6851-5).

Accordingly, there is a good correlation between raised levels ofcarbohydrate processing enzymes secreted by tumour cells, such asheparanases, and their metastatic potential (e.g. Vlodavsky et al.(1994) Invasion Metastasis 14:290-302; (1999) Nature Medicine5:793-802). Furthermore, the carbohydrate fragments generated byheparanase glycosidase action may also promote the cancer phenotypesince many of these fragments are growth-stimulatory. For example,heparanase activity can release heparan sulfate fragments which canincrease the potency of a variety of cell growth factors as well asstimulate cell growth when it itself is bound to appropriate cellsurface receptors (e.g. Folkman and Shing (1992) Adv. Exp. Med. Biol.313:355-64). Likewise, heparanase activity results in the release ofcertain growth factors that can stimulate angiogenesis and hence promotetumour growth (Bashlin et al. (1989) Biochemistry 28:1737-43).

Thus, inhibitors of ECM carbohydrate degradation may be potentanticancer agents. For example, sulfated oligosaccharide heparanaseinhibitors block tumour metastasis in some animal models (Vlodavsky etal., (1994) Invasion Metastasis 14:290-302; Parish et al., (1999) CancerRes. 59:3433-41). Interestingly, heparinomimetic compounds are beingdeveloped as anticoagulant and antiproliferative agents for the controlof thrombotic and proliferative disorders (Demir et al., Clin ApplThromb Hemost 2001 April;7(2):13140). Thus, heparanase inhibitors may bebeneficial for use in cardiovascular diseases, including blood clottingconditions, e.g. thromboembolic disease, arterial thrombosis andrestenosis, as agents that prevent the degradation of heparin.

WO01/35967 discloses the use of heparanase inhibitors for the treatmentor prevention of congestive heart failure e.g. primary cardiomyopathy.Associated conditions treated or prevented with such inhibitors includeperipheral odemas, pulmonary and hepatic congestion, dyspnoea,hydrothorax, sepsis and ascites. Renal disorders, e.g. renal diseaseassociated with diabetes or nocturia can also be treated.

Inflammatory conditions, including autoimmune disorders, e.g. MultipleSclerosis may also benefit from treatment with heparanase inhibitors(Parish et al., 1998, Immunol. Cell Biol. 76(1), 104-113).

Japanese patent application No: 63-073425 (publication no.01-247453)discloses (benzothiazol-2-yl)phenyl substituted phthalamides as lightstabilizers for use in thermoplastic polyester resins, including thecompound2-[4-(5-carboxy-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phenyl]-6-benzothiazolecarboxylicacid.

The present invention provides a novel class of compounds, which can beused as inhibitors of heparanase. Thus, these compounds provide theopportunity for establishing new treatments for cancer, angiogenesis,inflammatory conditions and cardiovascular diseases.

The invention provides a compound of formula (I) or a pharmaceuticallyacceptable salt or prodrug thereof:

wherein

X is O or S;

R¹ is a phthalimide carboxylic acid group of formula (II):

R is hydrogen, C₁-C₆ alkyl, aryl or C₁-C₃ alkylaryl;

R² is hydrogen, halogen, C₁-C₆ alkyl, OR⁵, a 5-membered heteroaryl ringor NR⁵R⁵ wherein the R⁵ substituents together with the nitrogen to whichthey are attached may form a 5- or 6-membered ring which may contain anadditional heteroatom selected from O, S and NR¹⁰;

R³ and R⁴ are independently hydrogen, halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂, NR⁷R⁸,NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo; or a 5- to 10-memberedheteroaryl ring which is optionally substituted by C₁-C₆ alkyl; or R³and R⁴ together may form a fused phenyl ring or a —O—(CH₂)_(x)—O— group,wherein x is 1 or 2;

R⁵ is independently hydrogen, C₃C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆alkyl optionally substituted by hydroxy, C₁-C₃ alkoxy, NR⁷R⁸, phenyl ora 5- or 6-membered heteroaryl ring, wherein phenyl is optionallysubstituted by one or more substituents selected from halogen, CF₃,OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and the heteroarylring is optionally substituted by C₁-C₆ alkyl;

R⁶ is C₁-C₆ alkyl, OR⁵, NR⁷R⁸ or phenyl optionally substituted by one ormore substituents selected from halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR¹⁰, CN, CHO,OCHF₂, NR⁷R⁸, NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo;

R⁷ and R⁸ are independently hydrogen, phenyl, a 5- to 10-memberedheterocyclic ring, C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substitutedby phenyl or a 5- to 10-membered heterocyclic ring, wherein in eachcase, the phenyl is optionally substituted by one or more substituentsselected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN andmethylenedioxo and the heterocyclic ring is optionally substituted byC₁-C₆ alkyl;

or R⁷ and R⁸ together with the nitrogen to which they are attached mayform a 5- or 6-membered heterocyclic ring which is optionallysubstituted by CONR¹⁰R¹⁰ and may optionally contain an additionalheteroatom selected from O, S and NR¹¹;

R⁹ is C₁-C₆ alkyl or phenyl optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo;

R¹⁰ is hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy;

R¹¹ is hydrogen, phenyl or C₁-C₃ alkyl optionally substituted by phenyl,wherein in each case the phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; and

p is 0, 1 or 2;

provided that the compound is not2-[4-(5-carboxy-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phenyl]-benzothiazolecarboxylicacid.

The compounds of the invention preferably have a molecular weight ofless than 800, more preferably less than 600.

The term “alkyl” as used herein whether on its own or as part of alarger group e.g. “alkoxy”, includes both straight and branched chainradicals. The term alkyl also includes those radicals wherein one ormore hydrogen atoms are replaced by fluorine. Alkenyl and alkynyl shouldbe interpreted accordingly.

The term “heteroaryl” as used herein includes a mono- or bicyclicaromatic ring containing up to three heteroatoms selected from oxygen,nitrogen and sulfur. Suitable ring systems include, for example,thiophene, benzofuran e.g. 2-benzofuran, benzothiophene, benzoxazolee.g. 2-benzoxazole, benzothiazole e.g. 2-benzothiazole, quinoline,isoquinoline, pyridine, pyrimidine, pyrazine, oxadiazole, imidazole,tetrazole, thiazole and furan.

The term “heterocyclic ring” as used herein includes both unsaturatedand saturated mono- or bicyclic cyclic ring systems. The ring maycontain up to 3 heteroatoms selected from oxygen, nitrogen and sulfur.Suitable ring systems include, for example, furan, thiophene, pyrrole,imidazole, oxadiazole, oxazole, thiazole, pyrazole, benzofuran,benzoxazole, benzothiazole, quinoline, isoquinoline, tetrazole,piperidine, piperizine and morpholine.

X is preferably O.

R is preferably hydrogen or C₁-C₃ alkyl. More preferably R is hydrogen.

R² is preferably hydrogen, OR⁵ or NR⁵R⁵. More preferably R is OR⁵ orNR⁵R⁵. Yet more preferably R² is —OCH₃ or —NH—(CH₂)₂—CH₃.

R³ is preferably hydrogen or halogen.

R⁴ is preferably hydrogen, halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, phenyl optionallysubstituted by one or more substituents selected from halogen, C₁-C₆alkyl optionally substituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵,COR⁶, CN, CHO, OCHF₂ and NR⁷R⁸; or a 5- to 10-membered heteroaryl ringwhich is optionally substituted by C₁-C₆ alkyl; or R³ and R⁴ togethermay form a fused phenyl ring.

R⁴ is more preferably COR⁶, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂ andNR⁷R⁸; or a 5- to 10-membered heteroaryl ring which is optionallysubstituted by C₁-C₆ alkyl. Yet more preferably, R⁴ is phenyl optionallysubstituted by one or more substituents selected from halogen, C₁-C₆alkyl optionally substituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵,COR⁶, CN, CHO, OCHF₂ and NR⁷R⁸; or a 5- to 10-membered heteroaryl ringwhich is optionally substituted by C₁-C₆ alkyl.

R⁵ is preferably hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆ alkyloptionally substituted by one of the following substituents, hydroxy,C₁-C₃ alkoxy or a 5- or 6-membered heteroaryl ring, wherein theheteroaryl ring is optionally substituted by C₁-C₆ alkyl.

R⁶ is preferably C₁-C₆ alkyl, OR⁵ or NR⁷R⁸. R⁶ is more preferably OR⁵ orNR⁷R⁸.

R⁷ and R⁸ are preferably independently hydrogen, or C₁-C₆ alkyloptionally substituted by phenyl or a 5- to 10-membered heterocyclicring, wherein the phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo and the heterocyclic ring is optionally substitutedby C₁-C₆ alkyl; or R⁷ and R⁸ together with the nitrogen to which theyare attached may form a 5- or 6-membered heterocyclic ring which isoptionally substituted by CONH₂ and may optionally contain an additionalheteroatom selected from O, S and NR¹¹.

R⁹ is preferably C₁-C₆ alkyl.

R¹⁰ is preferably C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy. More preferably R¹⁰ is —CH₃.

Preferably R¹ is meta to the benzoxazole or benzothiazole group.

Preferably R² is ortho or para to the benzoxazole or benzothiazolegroup.

Preferably R³ or R⁴ is located at position 5 or 6 on the benzoxazole orbenzothiazole group.

When R is aryl or alkylaryl, suitable aryl groups include, for example,phenyl.

When R² is a 5-membered heteroaryl ring, the heteroaryl ring may be, forexample, thiophene.

When R² is NR⁵R⁵ and the R⁵ substituents, together with the nitrogen towhich they are attached, form a 5- or 6-membered ring, the ring may be,for example, morpholine.

When R³ or R⁴ is a 5- to 10-membered heteroaryl ring, suitable ringsystems include, for example, thiophene, benzofuran e.g. 2-benzofuran,benzothiophene, benzoxazole e.g. 2-benzoxazole, benzothiazole e.g.2-benzothiazole, quinoline, isoquinoline, pyridine, pyrimidine,pyrazine, oxadiazole, imidazole, tetrazole and furan. Preferred ringsystems include thiophene, furan, benzothiophene and benzofuran.

When R⁵ is alkyl optionally substituted by a 5- or 6-membered heteroarylring, suitable heteroaryl groups include, for example, furan, thiophene,imidazole, oxadiazole, thiazole, tetrazole, pyridine, pyrimidine andpyrazine.

When R⁷ or R⁸ is a 5- to 10-membered heterocyclic ring, or alkyloptionally substituted by a 5- to 10-membered heterocyclic ring,suitable ring systems include, for example, furan, tetrahydrofuran,thiophene, pyrrole, imidazole, oxadiazole, oxazole, thiazole, pyrazole,benzofuran, benzoxazole, benzothiazole, quinoline, isoquinoline, andtetrazole. Preferred ring systems include furan, tetrahydrofuran andthiophene.

When R⁷ and R⁸ together with the nitrogen to which they are attachedform a 5- or 6-membered heterocyclic ring, the ring is preferablysaturated and may be, for example, piperazine, piperidine, ormorpholine. More preferably, the saturated ring is piperazine.

As described herein, for all aspects of the invention, reference tocompounds of formula (I) encompasses the pharmaceutically acceptablesalts and prodrugs thereof.

A specific group of compounds that may be mentioned include compounds offormula (I)a

wherein

X is O or S;

R¹ is a phthalimide carboxylic acid group of formula (II):

R² is hydrogen, halogen, C₁-C₆ alkyl, OR⁵ or NR⁵R⁵ wherein the R⁵substituents together with the nitrogen to which they are attached mayform a 5- or 6-membered ring which may contain an additional heteroatomselected from oxygen, nitrogen and sulfur;

R³ and R⁴ are independently hydrogen, halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁₋₆ alkyl, CF₃, OCF₃, OR⁵, COR⁶,CN, NHCOR⁷ and methylenedioxo, or a 5- to 10-membered mono- or bicyclicheteroaromatic ring containing up to three heteroatoms selected fromoxygen, nitrogen and sulfur which heteroaromatic ring may be substitutedby C₁-C₆ alkyl; or R³ and R⁴ together may form a fused phenyl ring;

R⁵ is independently hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆alkyl optionally substituted by hydroxy, C₁-C₃ alkoxy, NR⁷R⁸, phenyloptionally substituted by one or more substituents selected fromhalogen, C₁-C₆ alkyl, CF₃, OCF₃, CN, or a 5- or 6-memberedheteroaromatic group optionally substituted by C₁-C₆ alkyl;

R⁶ is C₁-C₆ alkyl, OR⁵ or NR⁷R⁸, or phenyl optionally substituted by oneor more substituents selected from halogen, C₁-C₆ alkyl, CF₃, OCF₃, OR⁵,COR⁶, CN, and NHCOR⁷;

R⁷ and R⁸ are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, phenyl optionallysubstituted by one or more substituents selected from halogen, CF₃,OCF₃, OR⁵, and CN, or a 5- to 10-membered mono or bicyclicheteroaromatic ring containing up to three heteroatoms selected fromoxygen, nitrogen and sulfur which heteroaromatic ring may be substitutedby C₁-C₆ alkyl; or R⁷ and R⁸ together with the nitrogen to which theyare attached may form a 5- or 6-membered ring which may contain anadditional heteroatom selected from oxygen, nitrogen and sulfur;

R⁹ is C₁-C₆ alkyl, or phenyl optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, OR⁵, and CN;

R¹⁰ is hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy; and

p is 0, 1 or 2;

provided that the compound is not2-[4-(5-carboxy-1,3dihydro-1,3-dioxo-2H-isoindol-2-yl)phenyl]-6-benzothiazolecarboxylicacid.

Specific compounds of formula (I) that may be mentioned include thoseprovided in the examples. A preferred list of specific compounds of theinvention include:

2-[3-(Naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;

2-[3-(5-Chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-(5-benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(benzofuran-2-yl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(2,4-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(5-Bromo-7-fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-3-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(6-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(6-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-N,N-dimethylaminophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid; and

2-[4-Methoxy-5-[5-(3,5-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid.

A more highly preferred list of specific compounds of the inventioninclude:

2-[2-Methoxy-5-[5-(benzofuran-2-yl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(5-Bromo-7-fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-3-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(6-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[3-(6-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[4-Propylamino-5-[5-(4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;

2-[2-Methoxy-5-[5-(4-N,N-dimethylaminophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid; and

2-[4-Methoxy-5-[5-(3,5-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid.

Suitable pharmaceutically acceptable salts of the compounds includethose derived from inorganic and organic bases. Examples of suitableinorganic bases for the formation of salts of compounds for thisinvention include the hydroxides, carbonates, and bicarbonates ofammonia, lithium, sodium, calcium, potassium, aluminium, iron,magnesium, zinc and the like. Salts can also be formed with suitableorganic bases. Such organic bases are well known in the art and mayinclude amino acids such as arginine and lysine, mono-, di-, ortri-hydroxyalkylamines such as mono-, di-, or tri-ethanolamine orcholine, mono-, di-, and tri-alkylamines, such as methylamine,dimethylamine, and trimethylamine, guanidine, N-methylglucosamine,N-methylpiperazine, morpholine, ethylenediamine, N-benzylphenethylamine,tris(hydroxymethyl) aminomethane, meglumine and the like.

Salts may be prepared in a conventional manner using methods well knownin the art, for example by treatment of a solution of the compound offormula (I) with a solution of the base, for example, potassium orsodium hydroxide, or potassium or sodium hydrogen carbonate.

The invention also includes prodrugs of the aforementioned compounds. Aprodrug is commonly described as an inactive or protected derivative ofan active ingredient or a drug, which is converted to the activeingredient or drug in the body. Examples of prodrugs includepharmaceutically acceptable esters, including C₁-C₆ alkyl esters andpharmaceutically acceptable amides, including secondary C₁-C₃alkylamides.

The compounds of this invention may be crystallised or recrystallisedfrom solvents such as aqueous and organic solvents. In such casessolvates may be formed. This invention includes within its scopestoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

In addition, the invention extends to active derivatives of theaforementioned compounds.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such forms, inparticular the pure isomeric forms (R or S). The different isomericforms may be separated or resolved one from the other by conventionalmethods, or any given isomer may be obtained by conventional syntheticmethods or by stereospecific or asymmetric syntheses. Where a compoundcontains an alkene moiety, the alkene can be presented as a cis or transisomer or a mixture thereof. When an isomeric form of a compound of theinvention is provided substantially free of other isomers, it willpreferably contain less than 5% w/w, more preferably less than 2% w/wand especially less than 1% w/w of the other isomers.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5%, e.g. 10 to 59% of a compound of formula (I).

The compounds of formula (I) can be prepared by art-recognizedprocedures from known or commercially available starting materials. Ifthe starting materials are unavailable from a commercial source, theirsynthesis is described herein, or they can be prepared by proceduresknown in the art.

The invention also provides a process for preparing a compound offormula (I), comprising: treating a compound of formula (III):

wherein R¹ is NH₂ or a protected derivative thereof and X, R², R³ and R⁴are as defined for formula (I), with a compound of formula (IV):

wherein R is as defined for formula (I) e.g. H, CH₃, C₂H₅, or CH₂Ph, byheating in a suitable acidic medium, for example, in a solution ofacetic acid or other suitable organic acid.

Alternatively, compounds of formula (I) may be prepared by heating acompound of formula (III) wherein R¹ is NH₂ and a compound of formula(IV) with an organic base, for example triethylamine in a suitablesolvent, for example, dimethylformamide, followed by heating in asuitable acidic medium, for example, acetic acid.

The compounds where R is C₁-C₆ alkyl, aryl or C₁-C₃ alkylaryl may beconverted to the compounds of formula (I) where R is H using methodswell known to those skilled in the art, for example, by hydrolysis withsodium hydroxide in water, or by hydrogenation (where R=CH₂Ph) withpalladium on charcoal catalyst/hydrogen. Certain basic conditions maycause phthalimide ring cleavage and re-cyclisation can then be carriedout using the acidic conditions described above.

A compound of formula (III) wherein R¹ is NH₂ may be prepared from acorresponding compound of formula (III), wherein R¹ is NO₂ and X, R², R³and R⁴ are as defined for formula (I), by methods well known to thoseskilled in the art, for example, by hydrogenation with palladium oncharcoal catalyst. The compounds of formula (III) wherein R¹ is NO₂, maybe prepared by treatment of a compound of formula (V):

wherein R¹ is NO₂ and R² is as defined for formula (I), with a compoundof formula (VI):

wherein X, R³and R⁴ are as defined for formula (I) by,

(i) heating in a condensation/cyclisation reaction using, for example,polyphosphoric acid or

(ii) by firstly coupling a compound of formula (VI) to a compound offormula (V) via either an ester/thioester or amide formation reaction,using methods well known to those of skill in the art, followed bydirect heating or heating with an acidic media with a suitable solventto effect cyclisation, for example, p-toluenesulfonic acid in toluene.Alternatively this may be achieved via oxidative cyclisation of a Schiffbase, derived from the condensation of the 2-aminophenol or2-aminothiophenol and aldehydes, using various oxidants such asPhI(OAc)₂, Pb(OAc)₄ or DDQ.

Compounds of formulae (V) and (VI) may be available through the usualcommercial sources. They and derivatives thereof may also be prepared bymethods well known to those skilled in the art.

The compounds of formula (II) where R³ or R⁴ is a halogen, may beconverted to other compounds of formula (III) where R³ or R⁴ is phenylor a 5- to 10-membered heteroaryl ring, either of which is optionallysubstituted as defined in formula (I). Thus, the compounds of formula(III) where R³ or R⁴ is halogen, may be further modified by a couplingreaction with compounds of formula (VII) using an appropriate catalystfor example tetrakis (triphenylphosphine) palladium:

wherein R¹² is phenyl or a 5- to 10-membered heteroaryl ring, either ofwhich is optionally substituted as defined in formula (I). Likewise asimilar palladium coupling reaction with halo aromatic compounds may beused with corresponding compounds of formula (III), wherein R¹ is NO₂,R² is OR⁵ or NR⁵R⁵ and R³ or R⁴ is independently B(OH)₂.

Furthermore, compounds of formula (III) where R² is halogen may beconverted to other compounds of formula (III) where R² is a 5-memberedheteroaryl ring by reaction with an alcohol or amine via a nucleophilicaromatic substitution or by a coupling reaction with compounds offormula (VII) wherein R¹² is a 5-membered heteroaryl ring, by the methoddescribed above.

During the synthesis of the compounds of formula (I), labile functionalgroups in the intermediate compounds, e.g. hydroxy, carboxy and aminogroups, may be protected. The protecting groups may be removed at anystage in the synthesis of the compounds of formula (I) or may be presenton the final compound of formula (I). A comprehensive discussion of theways in which various labile functional groups groups may be protectedand methods for cleaving the resulting protected derivatives is givenin, for example, Protective Groups in Organic Chemistry, T. W. Greeneand P. G. M. Wuts, (1991) Wiley-Interscience, New York, 2nd edition.

Further details for the preparation of compounds of formula (I) arefound in the examples.

Any novel intermediate compounds as described herein also fall withinthe scope of the present invention.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by combinatorial ‘split andmix’ approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I).

As mentioned above the compounds of the invention find use in therapy.Thus according to a further aspect the present invention provides acompound of formula (I), but without the proviso, for use in medicine.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining one of the aforementioned compounds(“active ingredient”) with standard pharmaceutical carriers or diluentsaccording to conventional procedures well known in the art. Theseprocedures may involve mixing, granulating and compressing or dissolvingthe ingredients as appropriate to the desired preparation.

According to a further aspect the present invention provides apharmaceutical composition comprising a compound of formula (I) butwithout the proviso, or a pharmaceutically acceptable salt or prodrugthereof, and a pharmaceutically acceptable carrier, excipient and/ordiluent.

The compounds or pharmaceutical compositions may be administered to asubject by any of the routes conventionally used for drugadministration, for example they may be adapted for oral (includingbuccal, sublingual), topical (including transdermal), nasal (includinginhalation), rectal, vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) administration to e.g.mammals including humans. The most suitable route for administration inany given case will depend on the particular compound or pharmaceuticalcomposition, the subject, and the nature and severity of the disease andthe physical condition of the subject. Such compositions may be preparedby any method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) excipient(s) ordiluent(s). Such carriers may be present as from about 1% up to about98% of the formulation. More usually they will form up to about 80% ofthe formulation.

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, impregnated dressings, sprays, aerosols or oilsand may contain appropriate conventional additives such aspreservatives, solvents to assist drug penetration and emollients inointments and creams. Such applications include those to the eye orother external tissues, for example the mouth and skin and thecompositions are preferably applied as a topical ointment or cream. Whenformulated in an ointment, the active ingredient may be employed, forexample, a paraffinic or a water-miscible ointment base. Alternatively,the active ingredient may be formulated in a cream with an oil-in-watercream base or a water-in-oil base. The composition may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions.

Pharmaceutical compositions adapted for topical administration to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solventPharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318, (1986).

Pharmaceutical compositions adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size, forexample, in the range 20 to 500 microns, which is administered by rapidinhalation through the nasal passage from a container of the powder heldclose up to the nose. Suitable compositions wherein the carrier is aliquid, for administration as a nasal spray or as nasal drops, includeaqueous or oil solutions of the active ingredient.

Pharmaceutical compositions adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or enemas. Suppositories will containconventional suppository bases, e.g. cocoa-butter or other glyceride.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or spraycompositions.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

For parenteral administration, fluid unit dosage forms are preparedutilizing the active ingredient and a sterile vehicle, water beingpreferred. The active ingredient, depending on the vehicle andconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the active ingredient can be dissolved in waterfor injection and filter sterilised before filling into a suitable vialor ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum The dry lyophilized powder is then sealedin the vial and an accompanying vial of water for injection may besupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the activeingredient is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The activeingredient can be sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the active ingredient.

The pharmaceutical compositions according to the invention arepreferably adapted for oral administration.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may also include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavouring agents. They may also contain therapeutically active agentsin addition to the compounds of the invention.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active ingredient, depending on the method ofadministration.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per dose. Such aunit may contain for example 0.1 mg/kg to 750 mg/kg, more preferably 0.1mg/kg to 10 mg/kg depending on the condition being treated, the route ofadministration and the age, weight and condition of the subject.Preferred unit dosage compositions are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient It will be recognized by one of skill in the artthat the optimal quantity and spacing of individual dosages of thecompounds of the invention will be determined by the nature and extentof the condition being treated, the form, route and site ofadministration, and the particular subject being treated, and that suchoptimums can be determined by conventional techniques. It will also beappreciated by one of skill in the art that the optimal course oftreatment, i.e. the number of doses of the aforementioned compoundsgiven per day for a defined number of days, can be ascertained by thoseskilled in the art using conventional course of treatment determinationtests.

No toxicological effects are indicated when the aforementioned compoundsof formula (I) are administered in the above mentioned dosage range.

The compounds of the invention or pharmaceutical compositions can beadministered simultaneously, separately or sequentially with one or moreother therapeutic agents.

By the term “treatment” is meant either prophylactic or therapeutic i.e.curative therapy.

The compounds of the present invention are useful in that they arecapable of inhibiting the enzyme heparanase. Thus, the compounds of theinvention can be used in the treatment of cancers, preferably for thetreatment of metastatic tumour cells. Examples of such types of cellsinclude, melanoma, mesothelioma, lymphoma, leukaemia, fibrosarcoma,rhabdomyosarcoma and mastocytoma. Types of cancer include, cancer of thecolorectum, prostate, lung (e.g. small cell lung and non-small celllung), breast, pancreas, kidney, liver, stomach (e.g. gastric,intestine, colon), bladder, skin, uterus, cervix or ovaries.

The compounds of the present invention can also be used in combinationwith one or more additional treatments or therapeutic compounds forcancer. Examples of such treatments include, surgery and radiationtherapy. Examples of therapeutic compounds include, but are not limitedto, cyclophosphamide (Cytoxan™); methotrexate (Methotrexate™);5-fluorouracil (5-FU); paclitaxel (Taxol™); docetaxel (Taxotere™);vincristine (Oncovin™); vinblastine (Velban™); vinorelbine (Navelbine™);doxorubicin (Adriamycin™); tamoxifen (Nolvadex™); toremifene(Fareston™);megestrol acetate(Megace™); anastrozole (Arimidex™); goserelin(Zoladex™); anti-HER2 monoclonal antibody (Herceptin™); capecitabine(Xeloda™) and raloxifene hydrochloride (Evista™).

The compounds of the present invention can also be used in the treatmentof angiogenesis and angiogenesis related disorders which includeangiogenesis associated with the growth of solid tumours andretinopathy.

The compounds of the present invention can also be used in combinationwith one or more additional treatments or therapeutic compounds forangiogenesis. Examples of such other therapeutic compounds include butare not limited to recombinant platelet-derived growth factor-BB(Regranex™).

The compounds of the present invention can also be used in the treatmentof inflammatory conditions, including autoimmune disorders, such as butnot limited to, rheumatoid arthritis, inflammatory bowel disease, woundhealing and Multiple Sclerosis.

The compounds of the present invention can also be used in the treatmentof cardiovascular diseases such as but not limited to blood clottingconditions, for example thromboembolic disease, arterial thrombosis andrestenosis.

The compounds of the invention can also be used in the treatment ofassociated conditions, such as, peripheral odemas, pulmonary and hepaticcongestion, dyspnoea, hydrothorax, sepsis and ascites.

The compounds of the invention can also be used in the treatment ofrenal disorders, e.g. renal disease associated with diabetes ornocturia.

In additional aspects, therefore, the present invention provides:

(i) the use of a compound of formula (I), but without the proviso, as aninhibitor of the enzyme heparanase.

(ii) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of cancer, preferablythe treatment of metastatic tumour cells. Examples of such types ofcells include melanoma, mesothelioma, lymphoma, leukaemia, fibrosarcoma,rhabdomyosarcoma and mastocytoma. Types of cancer include but are notlimited to, cancer of the colorectum, prostate, lung (e.g. small celllung and non-small cell lung), breast, pancreas, kidney, liver, stomach(e.g. gastric, intestine, colon), bladder, skin, uterus, cervix orovaries.

(iii) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of angiogenesis andangiogenesis related disorders which include angiogenesis associatedwith the growth of solid tumours and retinopathy.

(iv) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of inflammatoryconditions, including autoimmune conditions, such as but not limited torheumatoid arthritis, inflammatory bowel disease, wound healing andMultiple Sclerosis.

(v) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of cardiovasculardiseases, such as but not limited to, blood clotting conditions, forexample, thromoembolic disease, arterial thrombosis and restenosis.

(vi) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of conditions, suchas, peripheral odemas, pulmonary and hepatic congestion, dyspnoea,hydrothorax, sepsis and ascites.

(vii) the use of a compound of formula (I), but without the proviso, inthe manufacture of a medicament for the treatment of renal disorders,e.g. renal disease associated with diabetes or nocturia.

(viii) a method for the treatment of cancer, preferably the treatment ofmetastatic tumour cells which comprises the step of administering to apatient an effective amount of a compound of formula (I), but withoutthe proviso.

(ix) a method for the treatment of angiogenesis and angiogenesis relateddisorders, which include angiogenesis associated with the growth ofsolid tumours and retinopathy, which comprises the step of administeringto a patient an effective amount of a compound of formula (I), butwithout the proviso.

(x) a method for the treatment of inflammatory diseases, includingautoimmune disorders, such as but not limited to rheumatoid arthritis,inflammatory bowel disease, wound healing and Multiple Sclerosis, whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I), but without the proviso.

(xi) a method for the treatment of cardiovascular diseases, such as butnot limited to blood clotting conditions, for example thromboembolicdisease, arterial thrombosis and restenosis which comprises the step ofadministering to a patient an effective amount of a compound of formula(I), but without the proviso.

(xii) a method for the treatment of conditions, such as but not limitedto, peripheral odemas, pulmonary and hepatic congestion, dyspnoea,hydrothorax, sepsis and ascites which comprises the step ofadministering to a patient an effective amount of a compound of formula(I), but without the proviso.

(xiii) a method for the treatment of renal disorders, such as but notlimited to, renal disease associated with diabetes or nocturia whichcomprises the step of administering to a patient an effective amount ofa compound of formula (I), but without the proviso.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

EXAMPLES Example 12-[3-(Benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole5-carboxylicacid a) 2-(3-Aminophenyl)benzoxazole

3-Aminobenzoic acid (500 mg, 3.65 mmol) and 2-aminophenol (398 mg, 3.65mmol) were mixed with polyphosphoric acid (5 ml). The reaction washeated to 200° C. for 4 h. The reaction mixture was slowly poured intoice water (100 ml) and the resulting mixture basified with solid sodiumhydroxide. At pH5-6 the precipitate was filtered, washed with water anddried to give the subtitle compound, 625 mg (82%). ¹H NMR (CDCl₃) δ7.78(m, 1H), 7.65(d, J=7.5 Hz, 1H) 7.59(m, 2H), 7.36(m, 3H), 6.86(dd,J=2.2, 7.9Hz, 1H). MS 211 m/z (M+H)⁺.

b)2-[3-(Benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

2-(3-Aminophenyl)benzoxazole (500 mg, 2.4 mmol) and1,2,4-benzenetricarboxylic anhydride (546 mg, 2.4 mmol) in acetic acid(25 ml) were heated to reflux overnight. On cooling the precipitate wasfiltered, washed with acetic acid and dried to give the title compound710 mg (71%). ¹H NMR (CDCl₃) δ 8.44(dd, J=1.5, 7.9 Hz, 1H), 8.36(d,J=4.5 Hz, 2H) 8.28(dt, J=1.5, 7.2 Hz, 1H), 8.12(d, J=7.9 Hz, 1H),7.86-7.39(m, 4H), 7.45(m, 2H). MS 383 m/z (M−H)⁻.

Example 22-[3-(Naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Aminophenyl)naphth[2,3-d]oxazole

Prepared by the method of Example 1a), from 3-amino-2-naphthol (579 mg,3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitlecompound was obtained, 58 mg (6%). ¹H NMR (CDCl₃) δ 8.12(s, 1H), 7.90(m,3H), 7.65(dt, J=1.5, 7.5 Hz, 1H), 7.60(t, J=2.3 Hz, 1H), 7.42(m, 2H),7.27(t, J=7.9 Hz), 6.82(dd, J=2.3, 7.9 Hz). MS 261 m/z (M+H)⁺.

b)2-[3-(Naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)naphth[2,3-d]oxazole (36 mg, 0.14 mmol) and1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the titlecompound was obtained, 30 mg (44%). ¹H NMR (DMSO) δ 8.45(m, 2H), 8.38(d,3H), 8.30(s, 1H), 8.12(m, 3H), 7.82(m, 2H), 7.55(m, 2H). MS 433 m/z(M−H)⁻.

Example 32-[3-(6-Methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Aminophenyl)-6-methylbenzoxazole

Prepared by the method of Example 1a), from 2-amino-5-methylphenol (448mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitlecompound was obtained, 97 mg (12%). ¹H NMR (CDCl₃) δ 7.55(d, J=8.2 Hz,2H), 7.49(t, J=1.9 Hz, 1H), 7.30(s, 1H), 7.22(t, J=7.5 Hz, 1H),7.08(dd,J=1.1, 8.2 Hz, 1H), 6.76(dd, J=2.3, 7.9 Hz, 1H), 2.43(s, 3H). MS 225 m/z(M+H)⁺.

b)2-[3-(6Methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)-6-methylbenzoxazole (32 mg, 0.14 mmol) and1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the titlecompound was obtained, 42 mg (72%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.34(bd, 2H), 8.25(dt, 1H), 8.13(d, 1H), 7.75(m, 3H), 7.63(s, 1H),7.26(d, 1H), 2.50(s, 3H). MS 397 m/z (M−H)⁻.

Example 42-[3-(5-Chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Aminophenyl)-5-chlorobenzoxazole

Prepared by the method of Example 1a), from 2-amino-4-chlorophenol (522mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitlecompound was obtained, 114 mg (13%). ¹H NMR (CDCl₃) δ 7.81(bs, 1H),7.69-7.60(m, 3H), 7.49(t, J=7.1Hz), 7.41-7.27(m, 2H), 6.96(dd, J=2.6,7.9 Hz, 1H). MS 245, 247 m/z (M+H)⁺.

b)2-[3-(5-Chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)-5-chlorobenzoxazole (34 mg, 0.14 mmol) and1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the titlecompound was obtained, 38 mg (64%). ¹H NMR (DMSO) δ 8.48(dd, 1H),8.39(bd, 2H), 8.30(dt, 1H), 8.16(d, 1H), 8.00(d, 1H), 7.88(m, 4H),7.54(dd, 1H). MS 417 m/z (M−H)⁻.

Example 52-[3-(5-Phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Aminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (674mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitlecompound was obtained, 84 mg (8%). ¹H NMR (CDCl₃) δ 7.97(bs, 1H),7.70-7.57(m, 5H), 7.49(t, 1H), 7.45-7.35(m, 2H), 6.96(d, J=7.9 Hz, 1H).MS 287 m/z (M+H)⁺.

b)2-[3(5-Phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)-5-phenylbenzoxazole (40 mg, 0.14 mmol) and1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the titlecompound was obtained, 45 mg (70%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38(d, 2H), 8.30(dt, 1H), 8.12(m, 2H), 7.9(d, 1H), 7.78(m, 5H), 7.51(t,2H), 7.40(t, 1H). MS 459 m/z (M−H)⁻.

Example 62-[2-Methoxy-5-(naphth[2,3-d]oxazol-2yl)phenyl]-2,3dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-naphth[2,3-d]oxazole

Prepared by the method of Example 1a), from 3-amino-2-naphthol (476 mg,2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) thesubtitle compound was obtained, 120 mg (14%). ¹H NMR (CDCl₃) δ 8.06(s,1H), 7.92-7.83(m, 3H), 7.67(dd, J=1.9, 8.2 Hz, 1H), 7.60(d, J=1.9 Hz,1H), 7.38(m, 2H), 6.85(d, J=8.3 Hz, 1H), 3.88(s, 3H). MS 291 m/z (M+H)⁺.

b)2-[2-Methoxy-5-(naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)naphth[2,3-d]oxazole (67 mg, 0.23 mmol) and1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the tidecompound was obtained, 40 mg (37%). ¹H NMR (DMSO) δ 8.34(m, 4H), 8.24(d,1H), 8.15(s, 1H), 8.01(m, 3H), 8.43(m, 3H), 3.81(s, 3H). MS 463 m/z(M−H)⁻.

Example 72-[2-Methoxy-5-(6-methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-6-methylbenzoxazole

Prepared by the method of Example 1a), from 2-amino-5-methylphenol (368mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) thesubtitle compound was obtained, 75 mg (10%). ¹H NMR (CDCl₃) δ7.69-7.58(m, 4H), 7.35(bs, 1H), 6.92(d, J=7.9 Hz), 3.85(s, 3H), 2.51(s,3H). MS 255 m/z (M+H)⁺.

b)2-[2-Methoxy-5-(6-methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-6-methylbenzoxazole (58 mg, 0.23 mmol) and1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the tidecompound was obtained, 54 mg (55%). ¹H NMR (DMSO) δ 8.31(dd, 1H) 8.16(m,3H), 7.97(d, 1H), 7.50(d, 1H), 7.43(s, 1H), 7.32(d, 1H), 7.08(d, 1H),3.73(s, 3H), 2.33(s, 3H). MS 427 m/z (M−H)⁻.

Example 82-[2-Methoxy-5-(5-chlorobenzoxazolyl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-5-chlorobenzoxazole

Prepared by the method of Example 1a), from 4-chloro-2-aminophenol (429mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) thesubtitle compound was obtained, 111 mg (10%). ¹H NMR (CDCl₃) δ 7.70(d,J=1.9 Hz, 1H), 7.65(dd, J=1.9, 8.3 Hz, 1H), 7.59(d, J=1.9 Hz, 1H),7.46(d, J=8.3 Hz, 1H), 7.28(dd, J=1.9, 8.3 Hz, 1H), 6.90(d, J=8.3 Hz,1H), 3.96 (s, 3H). MS 275 m/z (M+H)⁺.

b)2-[2-Methoxy-5-(5-chlorobenzoxazolyl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-chlorobenzoxazole (63 mg, 0.23 mmol) and1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the titlecompound was obtained, 62 mg (60%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.33(m, 3H), 8.12(d, 1H), 7.89(d, 1H), 7.80(d, 1H), 7.47(m, 2H), 3.89(s,3H). MS 447 m/z (M−H)⁻.

Example 92-[2-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (554mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) thesubtitle compound was obtained, 111 mg (10%). ¹H NMR (CDCl₃) δ 7.84(s,1H), 7.72-7.38(m, 9H), 6.93(d, J=8.3 Hz, 1H), 3.96(s, 3H). MS 316 m/z(M+H)⁺.

b)2-[2-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method described in Example 1b), from2-(3-amino-4-methoxyphenyl)-5-phenylbenzoxazole (73 mg, 0.23 mmol) and1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the titlecompound was obtained, 50 mg (44%). ¹H NMR (DMSO) δ 8.46(dd, 1H),8.35(m, 3H), 8.13(d, 1H), 8.03(d, 1H), 7.84(d, 1H), 7.73(m, 3H), 7.49(m,3H), 7.39(t, 1H), 3.90(s, 3H). MS 489 m/z (M−H)⁻.

Example 102-[2-Methoxy-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-benzoxazole

Prepared by the method of Example 1a), from 2-aminophenol (326 mg, 2.9mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitlecompound was obtained, 97 mg (13%). ¹H NMR (CDCl₃) δ 7.66-7.45(m, 4H),7.24(m, 2H), 6.82(d, J=8.3 Hz, 1H), 3.86(s, 3H). MS 241 m/z (M+H)⁺.

b)2-[2-Methoxy-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)benzoxazole (55 mg, 0.23 mmol) and1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the titlecompound was obtained, 64 mg (67%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.32(m, 3H), 8.12(d, 1H), 7.78(m, 2H), 7.49(d, 1H), 7.41(m, 2H), 3.88(s,3H). MS 413 m/z (M−H)⁻.

Example 112-[2-Chloro-(5-chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-6-chlorophenyl)-5-chlorobenzoxazole

Prepared by the method of Example 1a), from 4-chloro-2-aminophenol (861mg, 6.0 mmol) and 4-chloro-3-aminobenzoic acid (1 g, 6.0 mmol) thesubtitle compound was obtained, 1.57 g (97%). ¹H NMR (CDCl₃) δ 7.73(d,J=2.3 Hz, 1H), 7.65(d, J=1.9 Hz, 1H), 7.55(dd, J=2.3 Hz, 1H), 7.49(d,1H), 7.33(dd, 1H). MS 279, 281 m/z (M+H)⁺.

b)2-[2-Chloro-(5-chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-6-chlorophenyl)-5-chlorobenzoxazole (327 mg, 1.2 mmol) and1,2,4-benzenetricarboxylic anhydride (250 mg, 1.3 mmol) the titlecompound was obtained, 180 mg (31%). ¹H NMR (DMSO) δ 8.33(d, 1H),8.25(dd, 1H), 8.16(bs, 1H), 8.12(dd, 1H), 7.95(d, 1H), 7.77(d, 1H),7.74(d, 1H), 7.63(d, 1H). MS 451, 452 m/z (M−H)⁻.

Example 122-[4-Chloro-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(2-Chloro-5-aminophenyl)benzoxazole

Prepared by the method of Example 1a), from 2-aminophenol (318 mg, 2.9mmol) and 4-chloro-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitlecompound was obtained, 583 mg (82%). ¹H NMR (CDCl₃) δ 7.81(t, 1H),7.59(t, 1H), 7.44(d, 1H), 7.36(d, 1H), 7.29(d, 1H), 6.74(dd, 2H). MS 245m/z (M+H)⁺.

b)2-[4-Chloro-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(2-chloro-5-aminophenyl)benzoxazole (250 mg, 1.0 mmol) and1,2,4-benzenetricarboxylic anhydride (196 mg, 1.0 mmol) the titlecompound was obtained, 350 mg (82%). ¹H NMR (DMSO) δ 8.50(dd, 1H),8.42(m, 2H), 8.18(d, 1H), 7.96(m, 3H), 7.83(dd, 1H), 7.56(m, 2H). MS 417m/z (M−H)⁻.

Example 132-[2-Methyl-5-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid a) 2-(3Amino-4-methylphenyl)-4-phenylbenzoxazole

Prepared by the method of Example 1a), from 2-amino-4-phenylphenol (1.23g, 7.0 mmol) and 3-amino-4-methylbenzoic acid (1.00 g, 7.0 mmol) thesubtitle compound was obtained, 814 mg (41%). ¹H NMR (DMSO) δ 8.01(d,1H), 7.82(d, 1H), 7.73(m, 2H), 7.67(dd, 1H), 7.49(m, 3H), 7.40(d, 1H),7.34(dd, 1H), 7.15(d, 1H), 2.50(s, 3H). MS 301 m/z (M+H)⁺.

b)2-[2-Methyl-5-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methylphenyl)-4-phenylbenzoxazole (167 mg, 0.9 mmol) and1,2,4-benzenetricarboxylic anhydride (250 mg, 0.9 mmol) the titlecompound was obtained, 340 mg (82%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.34(d, 2H), 8.26(dd, 1H), 8.13(d, 1H), 8.05(d, 1H), 7.85(d, 1H),7.73(m, 4H), 7.50(t, 1H), 7.39(t, 1H), 2.28(s, 3H). MS 473 m/z (M−H)⁻.

Example 142-[2-Methyl-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methylphenyl)benzoxazole

Prepared by the method of Example 1a), from 2-aminophenol (720 mg, 7.0mmol) and 3-amino-4-methylbenzoic acid (1.00 g, 7.0 mmol) the subtitlecompound was obtained, 942 mg (57%). ¹H NMR (DMSO) δ 7.67(m, 2H),7.42(s, 1H), 7.31(m, 2H), 7.24(d, 1H), 7.07(d, 1H), 2.43(s, 3H). MS 225m/z (M+H)⁺.

b)2-[2-Methyl-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methylphenyl)benzoxazole (250 mg, 1.1 mmol) and1,2,4-benzenetricarboxylic anhydride (214 mg, 1.1 mmol) the titlecompound was obtained. 375 mg (84%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.33(d, 2H), 8.23(dd, 1H), 8.12(d, 1H), 7.79(m, 2H), 7.68(d, 1H),7.44(m, 2H). MS 397 m/z (M−H)⁻.

Example 152-[2-Methoxy-5-[5-(benzofuran-2-yl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 4-Methoxy-3-nitro-benzoyl chloride

Oxalyl chloride (15.8 ml, 180 mmol) was added dropwise with stirring toa solution of 4-methoxy-3-nitrobenzoic acid (7.00 g, 36.00 mmol) in THFcontaining 10 μL DMF. After 1 h the solvent was removed under reducedpressure. The product was used directly in the next step.

b) N-(2-Hydroxy-5-bromophenyl)-3-nitro-4-methoxybenzamide

A solution of 4-methoxy-3-nitro-benzoyl chloride (7.12 g, 33.0 mmol) inTHF (50 ml) was added dropwise with stirring to a solution of4-bromo-2-aminophenol (6.20 g, 33.0 mmol) in THF (50 ml) containingtriethylamine (6.82 ml, 66.0 mmol). After addition was complete thereaction was stirred at room temperature overnight. The reaction mixturewas concentrated to approximately half the original volume and theprecipitate collected by filtration. The solid was washed with methanoland ether and dried under vacuum to give the subtitle compound as abrown solid (5.24 g, 42%). ¹H NMR (DMSO) δ 8.58(d, 1H), 8.36(dd, 1H),7.55(d, 1H), 6.96(m, 2H), 6.68(dd, 1H), 4.05(s, 3H).

c) 2-(3-Nitro-4-methoxyphenyl)-5-bromobenzoxazole

A suspension of N-(2-hydroxy-5-bromophenyl)-3-nitro-4-methoxybenzamide(5.24 g, 14.2 mmol) and toluenesulfonic acid monohydrate (5.36 g, 31.2mmol) in toluene (100 ml) was heated to reflux overnight. The cooledreaction mixture was washed with saturated sodium hydrogen carbonatesolution (care foaming) and the organic layer separated. The aqueouslayer was extracted with ethyl acetate (2×50 ml) and the combinedorganic layers dried over sodium sulfate and the solvent removed underreduced pressure. The residue was triturated with ether, filtered anddried under vacuum to give the subtitle compound as a pale pink solid(4.51 g, 93%). ¹H NMR (DMSO) δ 8.61(d, 1H), 8.42(dd, 1H), 8.05(d, 1H),7.79(d, 1H), 7.61(m, 2H), 4.05(s, 3H). MS m/z 349.0 (M+H)⁺.

d) 2-(3-Nitro-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole

2-(3-Nitromethoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) wassuspended in degassed ethylene glycol dimethyl ether (DME, 10 ml).Tetrakis (triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), 2M sodiumcarbonate (0.5 ml) and benzofuran-2-boronic acid (137 mg, 0.85 mmol)were added and the reaction was further degassed. The reaction washeated to reflux for 16 h. The cooled reaction mixture was diluted withwater (10 ml) and extracted with dichloromethane (2×10 ml). The combinedorganic extracts were dried over sodium sulfate, filtered and thesolvent removed under reduced pressure. The residue was triturated withmethanol (5 ml) and filtered. The solid was dried under vacuum to givethe subtitle compound (50 mg, 15%). ¹H NMR (DMSO) δ 8.63(d, 1H),8.44(dd, 1H), 8.29(d, 1H), 8.01(dd, 1H), 7.92(d, 1H), 7.69-7.59(m, 3H),7.54(s, 1H), 7.36-7.25(m, 2H), 4.04(s, 3H).

e) 2-(3-Amino-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole

A suspension of2-(3-nitro-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole (50 mg, 0.13mmol) in dioxane (10 ml) was placed under an atmosphere of argon.Palladium on carbon (10%) (10 mg) was added and the reaction purged withhydrogen and stirred at room temperature for 36 h. The reaction wasfiltered through a bed of celite and the filtrate concentrated to givethe subtitle compound (40 mg, 86%). MS m/z 357.1 (M+H)⁺.

f)2-[2-Methoxy-5-[(5-benzofuran-2-yl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

2-(3-Amino-4-methoxyphenyl-5-(benzofuran-2-yl)benzoxazole (40 mg, 0.11mmol) and 1,2,4-benzenetricarboxylic anhydride (23 mg, 0.12 mmol) inacetic acid (5 ml) were heated to reflux overnight On cooling theprecipitate was filtered, washed with acetic acid and dried under vacuumto give the title compound (30 mg, 51%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38-8.35(m, 3H), 8.29(d, 1H), 8.13(dd, 1H), 8.00(dd, 1H), 7.90(d, 1H),7.67(m, 2H), 7.55(s, 1H), 7.50(d, 1H), 7.36-7.25(m, 2H), 3.89(s, 3H). MSm/z 528.6 (M+H)⁺.

Example 162-[2-Methoxy-5-[5-(3-acetyl)phenylbenzoxazol-2yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-acetylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound wasobtained (89 mg, 26%). ¹H NMR (DMSO) δ 8.75(d, 1H), 8.46(dd, 1H),8.23(t, 1H), 7.98-7.96(m, 2H), 7.69-7.56(m, 3H), 7.27(d, 11), 4.08(s,3H), 2.68(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-acetylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-acetylphenyl)-benzoxazole (89 mg, 0.23mmol) the subtitle compound was obtained (80 mg, 97%). MS m/z 359.1(M+H)⁺.

c)2-[2-Methoxy-5-[5-(3-acetyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-(3-acetylphenyl)benzoxazole (80 mg, 0.22mmol) and 1,2,4-benzenetricarboxylic anhydride (47 mg, 0.25 mmol) thetitle compound was obtained (84 mg, 71%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.39-8.33(m, 3H), 8.26(s, 1H), 8.26(t, 1H), 8.14-8.11(m, 2H), 8.01(d,1H), 7.96(d, 1H), 7.88(d, 1H), 7.78(dd, 1H), 7.65(t, 1H), 7.50(d, 1H).MS m/z 533.0 (M+H)⁺.

Example 172-[2-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-[3,4-(methylenedioxy)phenyl]benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3,4-methylenedioxyboronic acid (141 mg, 0.85 mmol) the subtitle compoundwas obtained (127 mg, 38%). ¹H NMR (DMSO) δ 8.63(d, 1H), 8.45(dd, 1H),7.99(d, 1H), 7.82(d, 1H), 7.82(dd, 1H), 7.62(d, 1H), 7.33(d, 1H),7.21(dd, 1H), 7.02(d, 1H), 6.08(s, 2H), 4.05(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-[3,4-(methylenedioxy)phenyl]benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-[3,4-(methylenedioxy)phenyl]benzoxazole(135 mg, 0.35 mmol) the subtitle compound was obtained (120 mg, 95%) MSm/z 361.1 (M+H)⁺.

c)2-[2-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-[3,4-(methylenedioxy)phenyl]benzoxazole(120 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg,0.36 mmol) the title compound was obtained (82 mg, 46%). ¹H NMR (DMSO) δ8.45(dd, 1H), 8.37-8.32(m, 3H), 8.12(d, 1H), 7.96(d, 1H), 7.79(d, 1H),7.63(dd, 1H), 7.49(d, 1H), 7.33(d, 1H), 7.20(dd, 1H), 7.02(d, 1H),6.06(2H, s), 3.88(s, 3H). MS m/z 535.0 (M+H)⁺.

Example 182-[2-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-chlorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compound wasobtained (148 mg, 68%). ¹H NMR (CDCl₃) δ 8.74(s, 1H), 8.45(dd, 1H),7.90(d, 1H), 7.64(d, 1H), 7.55(d, 3H), 7.44(d, 2H), 7.26(d, 1H), 4.07(s,3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-chlorophenyl)-benzoxazole (134 mg, 0.35mmol) the subtitle compound was obtained (104 mg, 85%). MS m/z 351.1

c)2-[2-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole (104 mg, 0.30mmol) and 1,2,4-benzenetricarboxylic anhydride (58 mg, 0.33 mmol) thetitle compound was obtained (67 mg, 43%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38-8.33(m, 3H), 8.12(d, 1H), 8.05(d, 1H), 7.86(d, 1H), 7.77(d, 1H),7.70(dd, 1H), 7.55-7.48(m, 3H), 3.89(s, 3H). MS m/z 525.1 (M+H)⁺.

Example 192-[2-Methoxy-5-[5-(3,4-dimethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicadd a) 2-(3-Nitro-4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3,4-dimethoxyphenylboronic acid (157 mg, 0.85 mmol) the subtitlecompound was obtained (180 mg, 78%). ¹H NMR (CDCl₃) δ 8.74(d, 1H),8.44(dd, 1H), 7.91(d, 1H), 7.62(d, 1H), 7.57(dd, 1H), 7.25(d, 1H),7.19-7.14(m, 2H), 6.98(d, 1H), 4.07(s, 3H), 3.97(s, 3H), 3.94(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)benzoxazole (157 mg,0.39 mmol) the subtitle compound was obtained (137 mg, 93%). MS m/z377.1 (M+H)⁺.

c)2-[2-Methoxy-5-[5-(3,4-dimethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3,4-dimethoxyphenyl)benzoxazole (137 mg,0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (69 mg, 0.39 mmol)the title compound was obtained (101 mg, 51%). ¹H NMR (DMSO) δ 8.45(dd,1H), 8.37-8.32(m, 3H), 8.13(d, 1H), 8.02(d, 1H), 7.80(d, 1H), 7.68(dd,1H), 7.50(d, 1H), 7.30-7.24(m, 3H), 7.05(d, 1H), 3.88(s, 3H), 3.87(s,3H), 3.80(s, 3H). MS m/z 551.2 (M+H)⁺.

Example 202-[2-Methoxy-5-[5-(2-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(2-methoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and2-methoxyphenylboronic acid (130 mg, 0.85 mmol) the subtitle compoundwas obtained (163 mg, 76%). ¹H NMR (CDCl₃) δ 8.75(d, 1H), 8.45(dd, 1H),7.93(d, 1H), 7.61(d, 1H), 7.54(dd, 1H), 7.39-7.34(m, 2H), 7.25(d, 1H),7.09-7.01(m, 2H), 4.07(s, 3H), 3.83(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(2-methoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl-5-(2-methoxyphenyl)benzoxazole (130 mg, 0.35mmol) the subtitle compound was obtained (120 mg, 99%). MS m/z 347.1(M+H)⁺.

c)2-[2-Methoxy-5-[5-(2-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(2-methoxyphenyl)benzoxazole (346 mg, 0.40mmol) and 1,2,4-benzenetricarboxylic anhydride (77 mg, 0.44 mmol) thetitle compound was obtained (61 mg, 29%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38-8.33(m, 3H), 8.13(d, 1H), 7.82(d, 1H), 7.78(d, 1H), 7.49(d, 2H),7.36(m, 2H), 7.14(d, 1H), 7.06(t, 1H), 3.89(s, 3H), 3.79(s, 3H). MS m/z521.2 (M+H)⁺.

Example 212-[2-Methoxy-5-[5-(3,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3,4-dichlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3,4-dichlorophenylboronic acid (176 mg, 0.85 mmol) the subtitle compoundwas obtained (176 mg, 74%). ¹H NMR (CDCl₃) δ 8.74(d, 1H), 8.44(dd, 1H),7.89(d, 1H), 7.70(d, 1H), 7.65(d, 1H), 7.54(d, 2H), 7.44(dd, 1H),7.26(d, 1H), 4.08(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3,4-dichlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3,4-dichlorophenyl)benzoxazole (164 mg,0.39 mmol) the subtitle compound was obtained (114 mg, 76%). MS m/z385.0 (M+H)⁺.

c)2-[2-Methoxy-5-[5-(3,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3,4-dichlorophenyl)benzoxazole (114 mg,0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (588 mg, 0.33 mmol)the title compound was obtained (88 mg, 53%). ¹H NMR (DMSO) δ 8.45(dd,1H), 8.38-8.33(m, 3H), 8.13-8.10(m, 2H), 8.03(d, 1H), 7.76(d, 1H),7.77-7.75(m, 3H), 7.49(d, 1H), 3.89(s, 3H). MS m/z 559.1(M+H)⁺.

Example 222-[2-Methoxy-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-chloro-4-fluorophenylboronic acid (150 mg, 0.85 mmol) the subtitlecompound was obtained (163 mg, 72%). ¹H NMR (CDCl₃) δ 8.74(d, 1H),8.45(dd, 1H), 7.87(d, 1H), 7.64(m, 2H), 7.52(dd, 1H), 7.49-7.44(m, 1H),7.28-7.21(m, 2H), 4.08(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole (150mg, 0.38 mmol) the subtitle compound was obtained (107 mg, 76%). MS m/z369.1 (M+H)⁺.

c)2-[2-Methoxy-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-fluoro-3-chlorophenyl)benzoxazole (107mg, 0.29 mmol) and 1,2,4-benzenetricarboxylic anhydride (56 mg, 0.31mmol) the title compound was obtained (101 mg, 64%). ¹H NMR (DMSO) δ8.45(dd, 1H), 8.38-8.33(m, 3H), 8.12(d, 1H), 8.09(d, 1H), 7.98(dd, 1H),7.85(d, 1H), 7.79-7.71(m, 2H), 7.55(d, 1H), 7.49(d, 1H). MS m/z 543.1(M+H)⁺.

Example 232-[2-Methoxy-5-[5-(4-trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-trifluoromethylphenylboronic acid (161 mg, 0.85 mmol) the subtitlecompound was obtained (204 mg, 58%). ¹H NMR (DMSO) δ 8.64(d, 1H),8.46(dd, 1H), 8.16(d, 1H), 7.97(d, 2H), 7.92(d, 1H), 7.85-7.78(m, 3H),7.63(d, 1H), 4.05(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-trifluoromethylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-trifluoromethylphenyl)benzoxazole (113mg, 0.27 mmol) the subtitle compound was obtained (107 mg, 99%). MS m/z415.1 (M+H)⁺.

c)2-[2-Methoxy-5-[5-(4trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-trifluorophenyl)benzoxazole (107 mg,0.28 mmol) and 1,2,4-benzenetricarboxylic anhydride (53 mg, 0.30 mmol)the title compound was obtained (107 mg, 69%). ¹H NMR (DMSO) δ 8.45(dd,1H), 8.38-8.34(m, 3H), 8.14-8.10(m, 2H), 7.98(d, 2H), 7.89(d, 1H),7.84(d, 2), 7.77(dd, 1H), 7.50(d, 1H), 3.89(s, 3H). MS m/z 559.1 (M+H)⁺.

Example 242-[2-Methoxy-5-[5-[4-(1-hydroxyethyl)]phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(4-acetylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound wasobtained (119 mg, 36%). ¹H NMR (DMSO) δ 8.64(d, 1H), 8.46(dd, 1H),8.16(d, 1H), 8.06(d, 2H), 7.93-7.90(m, 3H), 7.81(dd, 1H), 7.63(d, 1H),4.05(s, 3H), 2.63(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-[4-(ethyl-2-hydroxy)phenyl]benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-methoxyphenyl)-5-(3-acetylphenyl)benzoxazole (51 mg, 0.13mmol) the subtitle compound was obtained (43 mg, 99%). MS m/z 389.1(M+H)⁺.

c)2-[2-Methoxy-5-[5-[4-(1-hydroxyethyl)]phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-[4-(ethyl-2-hydroxy)phenyl]benzoxazole (43mg, 0.12 mmol) and 1,2,4-benzenetricarboxylic anhydride (25 mg, 0.13mmol) the title compound was obtained (6 mg, 9%). ¹H NMR (DMSO) δ8.45(dd, 1H), 8.38-8.33(m, 3H), 8.12(d, 1H), 8.02(d, 1H), 7.84(d, 1H),7.74-7.67(m, 3H), 7.49(m, 3H), 5.84(q, 1H), 3.89(s, 3H), 1.51(d, 3H). MSm/z 517.1 (M+H)⁺.

Example 252-[2-Methoxy-5-[5-(4-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-methylphenylboronic acid (116 mg, 0.85 mmol) the subtitle compound wasobtained (201 mg, 66%). ¹H NMR (DMSO) δ 8.68(d, 1H), 8.51(dd, 1H),8.07(d, 1H), 7.90(d, 1H), 7.74-7.67(m, 3H), 7.36-7.33(d, 2H), 4.10(s,3H), 2.41(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-methylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-methylphenyl)benzoxazole (82 mg, 0.23mmol) the subtitle compound was obtained (59 mg, 99%). MS m/z 361.1(M+H)⁺.

c)2-[2-Methoxy-5-[5-(4-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-(4-methylphenyl)benzoxazole (59 mg, 0.18mmol) and 1,2,4-benzenetricarboxylic anhydride (38 mg, 0.20 mmol) thetitle compound was obtained (69 mg, 50%). ¹H NMR (DMSO) δ 8.45(d, 1H),8.38-8.32(m, 3H), 8.12(d, 1H), 7.99(d, 1H), 7.82(d, 1H), 7.69-7.61(m,3H), 7.49(d, 1H), 7.29(d, 2H), 3.89(s, 3H), 2.36(s, 3H). MS m/z 505.1(M+H)⁺.

Example 262-[2-Methoxy-5-[5-[(5-methyl)thiophen-2-yl]benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-[(5-methyl)thiophen-2-yl]benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and2-(5-methyl)thiopheneboronic acid (121 mg, 0.85 mmol) the subtitlecompound was obtained (301 mg, 96%). ¹H NMR (DMSO) δ 8.62(d, 1H),8.43(dd, 1H), 7.97(d, 1H), 7.80(d, 1H), 7.63(m, 2H), 7.38(d, 1H),6.84(dd, 1H), 4.05(s, 3H), 2.50(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-[(5-methyl)thiophen-2yl]benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-[(5-methyl)thiophen-2-yl]benzoxazole (75mg, 0.20 mmol) the subtitle compound was obtained (64 mg, 99%). MS m/z367.1 (M+H)⁺.

c)2-[2-Methoxy-5-[5-[(5-methyl)thiophen-2-yl]benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-[(5-methyl)thiophen-2-yl]benzoxazole (64mg, 0.19 mmol) and 1,2,4-benzenetricarboxylic anhydride (40 mg, 0.20mmol) the title compound was obtained (62 mg, 64%). ¹H NMR (DMSO) δ8.45(dd, 1H), 8.36-8.30(m, 3H), 8.11(d, 1H), 7.94(d, 1H), 7.77(d, 1H),7.61(dd, 1H), 7.49(d, 1H), 7.36(d, 1H), 6.84(dd, 1H), 3.89(s, 3H),2.50(s, 3H). MS m/z 511.1 (M+H)⁺.

Example 272-[2-Methoxy-5-[5-(4-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(4-methoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-methoxyphenylboronic acid (129 mg, 0.85 mmol) the subtitle compoundwas obtained (193 mg, 60%). ¹H NMR (DMSO) δ 8.63(d, 1H), 8.45(dd, 1H),7.99(d, 1H), 7.83(d, 1H), 7.67(d, 3H), 7.62(d, 1H), 7.05(d, 2H), 4.05(s,3H), 3.81(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-methoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-methoxyphenyl)benzoxazole (102 mg, 0.27mmol) the subtitle compound was obtained (103 mg, 99%). MS m/z 377.1(M+H)⁺.

c)2-[2-Methoxy-5-[5-(4-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-methoxyphenyl)benzoxazole (103 mg, 0.30mmol) and 1,2,4-benzenetricarboxylic anhydride (63 mg, 0.20 mmol) thetitle compound was obtained (91 mg, 58%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38-8.32(m, 3H), 8.12(d, 1H), 7.96(d, 1H), 7.80(d, 1H), 7.69-7.63(m,3H), 7.49(d, 1H), 7.65(d, 2H), 3.89(s, 3H), 3.81(s, 3H). MS m/z 521.1(M+H)⁺.

Example 282-[2-Methoxy-5-[5-(3-cyano)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-cyanophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-cyanophenylboronic acid (126 mg, 0.86 mmol) the subtitle compound wasobtained (65 mg, 31%). ¹H NMR (DMSO) δ 8.75(d, 1H), 8.57(dd, 1H),8.35(t, 1H), 8.29(d, 1H), 8.21(dt, 1H), 8.00(d, 1H), 7.97(dt, 1H),7.93(d, 1H), 7.80(t, 1H), 7.74(d, 1H), 4.17(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-cyanophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-cyanophenyl)benzoxazole (50 mg, 0.14mmol) the subtitle compound was obtained (33 mg, 71%). The product wasused directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3-cyano)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-cyanophenyl)benzoxazole (31 mg, 0.09mmol) and 1,2,4-benzenetricarboxylic anhydride (17 mg, 0.09 mmol) thetitle compound was obtained, (14 mg, 30%). ¹H NMR (DMSO) δ 8.47(dd, 1H),8.38(d, 1H), 8.35(q, 2H), 8.25(t, 1H), 8.17(d, 1H), 8.13(d, 1H),8.11(dt, 1H), 7.90(d, 1H), 7.85(d, 1H), 7.80(dd, 1H), 7.70(t, 1H),7.50(d, 1H), 3.90(s, 3H). MS 516 m/z (M+H)⁺.

Example 292-[2-Methoxy-5-[5-(3-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-methylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-methylphenylboronic acid (117 mg, 0.86 mmol) the subtitle compound wasobtained, (69 mg, 33%). ¹H NMR (DMSO) δ 8.64(d, 1H), 847(dd, 1H),8.14(d, 1H), 7.86(d, 1H), 7.72(dd, 1H), 7.64(d, 1H), 7.55(m, 2H),7.39(t, 1H), 7.22(d, 1H), 4.07(s, 1H), 2.40(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-methylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-methylphenyl)benzoxazole (61 mg, 0.17mmol) the subtitle compound was obtained, (47 mg, 84%). The product wasused directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-methylphenyl)benzoxazole (44 mg, 0.13mmol) and 1,2,4-benzenetricarboxylic anhydride (25 mg, 0.13 mmol) thetitle compound was obtained, (31 mg, 46%). ¹H NMR (DMSO) δ 8.46(dd, 1H),8.38(d, 1H), 8.34(q, 2H), 8.13(d, 1H), 8.02(d, 1H), 7.84(d, 1H),7.68(dd, 1H), 7.52(m, 3H), 7.48(t, 1H), 7.20(d, 1H), 3.89(s, 3H),2.40(s, 3H). MS 505 m/z (M+H)⁺.

Example 302-[2-Methoxy-5-[5-(3-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-methoxyphenylboronic acid (131 mg, 0.86 mmol) the subtitle compoundwas obtained, (98 mg, 45%). ¹H NMR (DMSO) δ 8.71(d, 1H), 8.52(dd, 1H),8.35(t, 1H), 8.17(d, 1H), 7.93(d, 1H), 7.82(dd, 1H), 7.69(d, 1H),7.48(t, 1H), 7.36(m, 2H), 7.03(dd, 1H), 4.12(s, 3H), 3.90(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (87 mg, 0.23mmol) the subtitle compound was obtained, (66 mg, 82%). The product wasused directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (62 mg, 0.18mmol) and 1,2,4-benzenetricarboxylic anhydride (35 mg, 0.18 mmol) thetitle compound was obtained, (47 mg, 50%). ¹H NMR (DMSO) δ 8.35(dd, 1H),8.28(d, 1H), 8.22(q, 2H), 8.02(d, 1H), 7.93(d, 1H), 7.72(d, 1H),7.60(dd, 1H), 7.40(d, 1H), 7.30(t, H), 7.17(m, 2H), 6.85(dd, 1H),3.79(s, 3H), 3.75(s, 3). MS 521 m/z (M+H)+.

Example 312-[2-Methoxy-5-[5-(3-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-fluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound wasobtained, (103 mg, 49%). ¹H NMR (DMSO) δ 8.59(d, 1H), 8.40(dd, 1H),8.08(d, 1H), 7.82(d, 1H), 7.72(dd, 1H), 7.52(m, 4H), 7.17(dt, 1H),4.02(s, 3H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-fluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-fluorophenyl)benzoxazole (94 mg,0.26mmol) the subtitle compound was obtained, (73 mg, 85%). The productwas used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-fluorophenyl)benzoxazole (67 mg, 0.20mmol) and 1,2,4-benzenetricarboxylic anhydride (38 mg, 0.20 mmol) thetitle compound was obtained, (65 mg, 64%). ¹H NMR (DMSO) δ 8.33(dd, 1H),8.28(d, 1H), 8.22(q, 2H), 8.02(d, 1H), 7.98(d, 1H), 7.74(d, 1H),7.64(dd, 1H), 7.45(m, 3H), 7.38(d, 1H), 7.10(dt, 1H), 3.77(s, 3H). MS509 m/z (M+H)⁺.

Example 322-[2-Methoxy-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3-chlorophenylboronic acid (134 mg, 0.86 mmol) the subtitle compound wasobtained, (72 mg, 33%). ¹H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H),8.19(d, 1H), 7.95(d, 1H), 7.88(t, 1H), 7.83(dd, 1H), 7.79(d, 1H),7.70(d, 1H), 7.58(t, 1H), 7.52(d, 1H), 4.12(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-chlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-chlorophenyl)benzoxazole (62 mg, 0.16mmol) the subtitle compound was obtained, (44 mg, 77%). The product wasused directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-chlorophenyl)benzoxazole (42 mg, 0.12mmol) and 1,2,4-benzenetricarboxylic anhydride (23 mg, 0.12 mmol) thetitle compound was obtained, (33 mg, 53%). ¹H NMR (DMSO) δ 8.48(dd, 1H),8.42(d, 1H), 8.37(q, 2H), 8.16(d, 1H), 8.13(d, 1H), 7.89(d, 1H), 7.84(t,1H), 7.75(m, 2H), 7.52(m, 3H), 3.91(s, 3H). MS 525 m/z (M+H)⁺.

Example 332-[2-Methoxy-5-[5-(4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(4-fluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound wasobtained, (135 mg, 65%). ¹H NMR (DMSO) δ 8.64(d, 1H), 8.45(dd, 1H),8.05(d, 1H), 7.87(d, 2H), 7.78(dd, 1H), 7.72(dd, 1H), 7.62(d, 2H),7.33(t, 1H), 4.08(s, 3H).

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-fluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-fluorophenyl)benzoxazole (122 mg, 0.33mmol) the subtitle compound was obtained, (66 mg, 59%). The product wasused directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-fluorophenyl)benzoxazole (55 mg, 0.16mmol) and 1,2,4-benzenetricarboxylic anhydride (31 mg, 0.16 mmol) thetitle compound was obtained, (41 mg, 49%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.38(d, 1H), 8.34(q, 2H), 8.12(d, 1H), 8.02(d, 1H), 7.84(d, 2H),7.78(dd, 1H), 7.68(dd, 1H), 7.49(d, 2H), 7.32(t, 1H), 3.88(s, 3H). MS509 m/z (M+H)⁺.

Example 342-[2-Methoxy-5-[5-(2,4-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro methoxyphenyl)-5-(2,4-difluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and2,4-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compoundwas obtained, (57 mg, 26%). ¹H NMR (DMSO) δ 8.71(d, 1H), 8.53(dd, 1H),8.01(s, 1H), 7.97(d, 1H), 7.70(m, 3H), 7.48(dt, 1H), 7.30(dt, 1H),4.12(s, 3H). MS 383 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(2,4-difluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(2,4-difluorophenyl)benzoxazole (50 mg,0.15 mmol) the subtitle compound was obtained, (50 mg, 95%). The productwas used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(2,4-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(2,4-difluorophenyl)benzoxazole (50 mg,0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (27 mg, 0.16 mmol)the title compound was obtained, (25 mg, 33%). ¹H NMR (DMSO) δ 8.45(dd,1H), 8.38(d, 1H), 8.35(q, 2H), 8.12(d, 1H), 7.91(s, 1H), 7.87(d, 1H),7.67(dt, 1H), 7.57(dt, 1H), 7.50(d, 1H), 7.41(m, 1H), 7.23(dt, 1H),3.89(s, 3H). MS 527 m/z (M+H)⁺.

Example 352-[2-Methoxy-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3,5-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compoundwas obtained, (120 mg, 64%). ¹H NMR (DMSO) δ 8.70(d, 1H), 8.52(dd, 1H),8.26(d, 1H), 7.96(d, 1H), 7.88(dd, 1H), 7.69(d, 1H), 7.61(dd, 2H),7.33(tt, 1H), 4.12(s, 3H). MS 383 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole (120 mg,0.31 mmol) the subtitle compound was obtained, (90 mg, 82%). The productwas used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole (90 mg,0.26 mmol) and 1,2,4-benzenetricarboxylic anhydride (49 mg, 0.28 mmol)the title compound was obtained, (58 mg, 43%). ¹H NMR (DMSO) δ 8.60(dd,1H), 8.52(d, 1H), 8.49(d, 2H), 8.31(d, 1H), 8.26(d, 1H), 8.01(d, 1H),7.93(dd, 1H), 7.69(dd, 2H), 7.64(d, 1H), 7.40(tt, 1H), 4.04(s, 3H). MS527 m/z (M+H)⁺.

Example 362-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-(4-trifluoromethoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-trifluoromethoxyphenylboronic acid (177 mg, 0.86 mmol) the subtitlecompound was obtained, (119 mg, 48%). ¹H NMR (DMSO) δ 8.70(s, 1H),8.52(d, 1H), 8.16(s, 1H), 7.93(d, 3H), 7.81(d, 2H), 7.68(d, 1H), 7.55(d,1H), 4.12(s, 3H). MS 431m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(4trifluoromethoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-trifluoromethoxyphenyl)benzoxazole (127mg, 0.30 mmol) the subtitle compound was obtained, (90 mg, 76%). Theproduct was used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(4-trifluoromethoxyphenyl)benzoxazole (90mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (43 mg, 0.25mmol) the title compound was obtained, (52 mg, 40%). ¹H NMR (DMSO) δ8.32(dd, 1H), 8.25(d, 1H), 8.22(q, 2H), 7.99(d, 1H), 7.95(d, 1H),7.76(s, 1H), 7.73(s, 2H), 7.59(dd, 1H), 7.36(dd, 3H), 3.77(s, 3H). MS575 m/z (M+H)⁺.

Example 372-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid a)2-(3-Nitro-4-methoxyphenyl)-5-(3-trifluoromethylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200mg, 0.57mmol) and3-trifluoromethylphenylboronic acid (163 mg, 0.86 mmol) the subtitlecompound was obtained, (120 mg, 51%). ¹H NMR (DMSO) δ 8.70(s, 1H),8.52(d, 1H), 8.24(s, 1H), 8.11(s, 1H), 7.97(d, 1H), 7.86(d, 1H), 7.81(s,2H),7.68(d, 1H), 4.11(s, 3H). MS 415 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-trifluoromethylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-trifluoromethyl phenyl)benzoxazole (120mg, 0.29 mmol) the subtitle compound was obtained, (110 mg, 99%). Theproduct was used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(3-trifluoromethylphenyl)benzoxazole (110mg, 0.29 mmol) and 1,2,4-benzenetricarboxylic anhydride (55 mg, 0.31mmol) the title compound was obtained, (78 mg, 49%). ¹H NMR (DMSO) δ8.45(dd, 1H), 8.38(d, 1H), 8.34(q, 2H), 8.15(d, 1H), 8.12(d, 1H),8.05(s, 2H), 7.88(d, 1H), 7.75(s, 2H), 7.50(d, 1H), 3.89(s, 3H). MS575m/z (M+H)⁺.

Example 382-[2-Methoxy-5-[5-(2,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(2,4-dichlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and2,4-dichlorophenylboronic acid (164 mg, 0.86 mmol) the subtitle compoundwas obtained, (148 mg, 62%). ¹H NMR (DMSO) δ 8.69(s, 1H), 8.51(d, 1H),7.93(d, 1H), 7.84(s, 1H), 7.60(m, 3H), 4.12(s, 3H). MS 415 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(2,4-dichlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(2,4-dichlorophenyl)benzoxazole (148 mg,0.36 mmol) the subtitle compound was obtained, (110 mg, 80%). Theproduct was used directly in the next step without purification.

c)2-[2-Methoxy-5-[5-(2,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl)-5-(2,4-dichlorophenyl)benzoxazole (110 mg,0.29 mmol) and 1,2,4-benzenetricarboxylic anhydride (55 mg, 0.31 mmol)the title compound was obtained, (62 mg, 39%). ¹H NMR (DMSO) δ 8.36(dd,1H), 8.29(d, 1H), 8.26(q, 2H), 8.03(d, 1H), 7.77(d, 1H), 7.74(d, 1H),7.69(s, 1H), 7.45(s, 2H), 7.41(d, 1H), 7.36(dd, 1H), 3.80(s, 3H). MS 575m/z (M+H)⁺.

Example 392-[2-Propargyloxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1Hisoindole-5-carboxylic acid a)2-(3-Nitro-4-propargyloxy)-5-phenylbenzoxazole

Potassium carbonate (330 mg, 2.4 mmol) was added in one portion to astirred solution of 2-(3-nitro-4-fluoro)-5-phenylbenzoxazole (400 mg,1.2 mmol) and propargyl alcohol (0.07 ml, 1.2 mmol) in DMF (4 ml) atroom temperature under argon. The resulting mixture was heated at 85° C.for 16 h. After being allowed to cool to room temperature the mixturewas poured into water (5 ml) and 10% aqueous hydrochloric acid was addeduntil pH 3. Then, the aqueous mixture was extracted with EtOAc (3×5 ml)and the combined organic extracts were washed with 10% aqueoushydrochloric acid (10 ml), brine (5 ml), dried (Na₂SO₄) and evaporatedunder reduced pressure to give the subtitle compound (408 mg, 92%) as abrown solid which was sufficiently pure (by TLC and ¹H NMR spectroscopy)to be used in the next step, R_(F)(3:1 Petrol-EtOAc) 0.41; ¹H NMR (DMSO)δ 8.69(1H, d, J=2.5 Hz, Ar), 8.52(1H, dd, J=2.5, 9.0 Hz, Ar), 8.10(1H,d, J=1.5 Hz, Ar), 7.92(1H, d, J=8.5 Hz, Ar), 7.79-7.69(4H, m, Ar),7.54(2H, t, J=7.0 Hz, Ar), 7.43(1H, t, J=7.0 Hz, Ar), 5.21(2H, d, J=2.5Hz, CH₂), 3.85(1H, t, J=2.5 Hz, CH).

b) 2-(3-Amino-4-propargyloxy)-5-phenylbenzoxazole

Tin(II) chloride dihydrate (148 mg, 0.7 mmol) was added in one portionto a stirred suspension of2-(3-nitro-4-propargyloxy)-5-phenylbenzoxazole (100 mg, 0.3 mmol),powdered zinc (43 mg, 0.7 mmol) and 37% aqueous hydrochloric acid (0.2ml, 4.9 mmol) in AcOH (1.5 ml) at room temperature. After 2 h, 6 Maqueous sodium hydroxide solution was added until pH 10 was obtained andthe mixture was extracted with EtOAc (3×3 ml), dried (Na₂SO₄) andevaporated under reduced pressure to give the crude subtitle compound(62 mg, 67%) as a pale yellow solid which was sufficiently pure (by TLCand ¹H NMR spectroscopy) to be used in the next step, R_(F)(3:1Petrol-EtOAc) 0.36; ¹H NMR (CDCl₃) δ 7.84(1H, d, J=1.0 Hz, Ar),7.60-7.52(4H, m, Ar), 7.49-7.44(2H, m, Ar), 7.39(2H, brt, J=7.0 Hz, Ar),7.28 (1H, tt (appearing as a t), J=7.5 Hz, Ar), 6.93(1H, d, J=8.0 Hz,Ar), 4.73(2H, d, J=2.5 Hz, CH₂), 3.93(2H, brs, NH₂), 2.49(1H, t, J=2.5Hz, CH).

c)2-[2-Propargyloxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-propargyloxy)-5-phenylbenzoxazole (62 mg, 0.2 mmol) and1,2,4-benzene tricarboxylic anhydride (35 mg, 0.2 mmol) in AcOH (1 ml)gave the title compound (27 mg, 29%) as a brown solid, ¹H NMR (DMSO) δ13.87(1H, brs, CO₂H), 8.52-8.40(4H, m, Ar), 8.18(1H, d, J=8.0 Hz, Ar),8.10(1H, d, J=1.5 Hz, Ar), 7.91(1H, d, J=8.5 Hz, Ar), 7.81-7.74(3H, m,Ar),7.62-7.52(3H, m, Ar), 7.44(1H, brt, J=7.0 Hz, Ar), 5.04(2H, d, J=2.0Hz, CH₂), 3.72(1H, t, J=2.0 Hz, CH).

Example 402-[2-Ethoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-ethoxyphenyl)-5-phenylbenzoxazole

Sodium ethoxide (41 mg, 0.6 mmol) was added portionwise to a stirredsuspension of 2-(3-nitro-4-fluoro)-5-phenylbenzoxazole (200 mg, 0.6mmol) in EtOH (2 ml) at 0° C. under argon. When gas evolution hadvisibly ceased the mixture was allowed to warm to room temperature andthen heated at 85° C. for 1 h. After being allowed to cool to roomtemperature the mixture was carefully diluted with water (5 ml) andextracted with EtOAc (3×5 ml). The combined organic extracts were washedwith brine (5 ml), dried (Na₂SO₄) and evaporated under reduced pressureto give the crude subtitle compound (207 mg, 96%) as a pale brown solidwhich was sufficiently pure (by TLC and ¹H NMR spectroscopy) to be usedin the next step, R_(F)(3:1 Petrol-EtOAc) 0.37; ¹H NMR (DMSO) δ 8.65(1H,d, J=2.0 Hz, Ar), 8.45(1H, dd, J=2.5, 9.0 Hz, Ar), 8.08(1H, d, J=1.5 Hz,Ar), 7.90(1H, d, J=8.5 Hz, Ar), 7.79-7.74(3H, m, Ar), 7.63(1H, d, J=9.0Hz, Ar), 7.54(2H, t, J=7.0 Hz, Ar), 7.43(1H, t, J=7.0 Hz, Ar), 4.38(2H,q, J=7.0 Hz, CH₂), 1.43(1H, t, J=7.0 Hz, CH₃).

b) 2-(3Amino-4ethoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from palladium (10 mol %) oncarbon (10 mg, 0.1 mmol) and2-(3-nitro-4ethoxyphenyl)-5-phenylbenzoxazole (100 mg, 0.3 mmol) indioxane (1 ml) which gave the crude subtitle compound (51 mg, 56%) as awhite solid which was sufficiently pure (by TLC and ¹H NMR spectroscopy)to be used in the next step, R_(F)(2:1 Petrol-EtOAc) 0.50; ¹H NMR(CDCl₃) δ 7.92(1H, d, J=1.0, Ar), 7.68-7.60(4H, m, Ar), 7.57-7.51(2H, m,Ar), 7.47(2H, brt, J=7.0 Hz, Ar), 7.36(1H, tt, J=1.0, 6.5 Hz, Ar),6.89(1H, d, J=8.5 Hz, Ar), 4.16(2H, q, J=7.0 Hz, CH₂), 3.98(2H, brs,NH₂), 1.49(1H, t, J=2.5 Hz, CH₃).

c)2-[2-Ethoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-ethoxy)-5-phenylbenzoxazole (43 mg, 0.1 mmol) and1,2,4-benzene tricarboxylic anhydride (25 mg, 0.1 mmol) in AcOH (1 ml)gave the title compound (27 mg, 41%) as a white solid, ¹H NMR δ (DMSO)13.88(1H, brs, CO₂H), 8.49(1H, d, J=8.0 Hz, Ar), 8.40-8.36(3H, m, Ar),8.07(1H, s, Ar), 7.90(1H, d, J=8.5 Hz, Ar), 7.79-7.72(3H, m, Ar),7.54(3H, brt, J=7.0 Hz, Ar), 7.45-7.40(1H, m, Ar), 4.25(2H, q, J=6.5 Hz,CH₂), 1.26(3H, t, J=6.5 Hz, CH₃).

Example 412-[2-(2-Methoxyethylamino)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-[3-Nitro-4-(2-methoxyethylamino)]-5-phenylbenzoxazole

2-Methoxyethylamine (2.0 ml, 23.9 mmol) was added dropwise to2-(3-nitro-4-fluoro)-5-phenylbenzoxazole (200 mg, 0.6 mmol) withstirring at room temperature under argon. The resulting suspension wasstirred at room temperature for 15 min. EtOAc (10 ml) was then added andthe mixture was washed with 10% aqueous hydrochloric acid (10 ml), brine(10 ml), dried (Na₂SO₄) and evaporated under reduced pressure to givethe crude subtitle compound (235 mg, 100%) as an orange solid which wassufficiently pure (by TLC and ¹H NMR spectroscopy) to be used in thenext step, R_(F)(2:1 Petrol-EtOAc) 0.18; ¹H NMR (CDCl₃) δ 9.01(1H, d,J=2.5 Hz, Ar), 8.49(1H, brt, J=˜4.5 Hz, NH), 8.24(1H, dd, J=2.0, 9.0 Hz,Ar), 7.85(1H, d, J=1.0 Hz, Ar), 7.58-7.48(4H, m, Ar), 7.43-7.38(2H, m,Ar), 7.32-7.27(1H, m, Ar), 6.95(1H, d, J=9.0 Hz, Ar), 3.65(2H, t, J=5.5Hz, CH₂O), 3.52 (2H, td (appearing as a q), J=5.5 Hz, CH₂N), 3.39(3H, s,OMe).

b) 2-[3-Amino-4-(2-methoxyethylamino)]-5-phenylbenzoxazole

Prepared by the method of Example 15e), from palladium (10 mol %) oncarbon (10 mg, 0.1 mmol) and2-[3-nitro-4-(2-methoxyethylamino)]-5-phenylbenzoxazole (100 mg, 0.3mmol) in dioxane (1 ml) which gave the crude subtitle compound (75 mg,81%) as a white solid which was sufficiently pure (by TLC and ¹H NMRspectroscopy) to be used in the next step, ¹H NMR (CDCl₃) δ 7.89(1H, d,J=1.0 Hz, Ar), 7.77(1H, dd, J=2.0, 8.5 Hz, Ar), 7.65-7.62(3H, m, Ar),7.58-7.51(2H, m, Ar), 7.46(2H, brt, J=7.0 Hz, Ar), 7.36(1H, brt, J=7.0Hz, Ar), 7.36 (1H, tt (appearing as a brt), J=7.0 Hz, Ar), 6.73(1H, d,J=8.5 Hz, Ar), 3.70(2H, t, J=5.5 Hz, CH₂O), 3.43(3H, s, OMe), 3.39(2H,t, J=5.5 Hz, CH₂N).

c)2-[2-(2-Methoxyethylamino)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-[3-amino-4-(2-methoxyethylamino)]-5-phenylbenzoxazole (54 mg, 0.2mmol) and 1,2,4-benzene tricarboxylic anhydride (29 mg, 0.2 mmol) inAcOH (1 ml) gave the title compound (10 mg, 12%) as a pale brown solid,¹H NMR (DMSO) δ 13.40 (1H, brs, CO₂H), 8.52 (1H, s, Ar), 8.29-8.20 (4H,m, Ar), 8.11 (1H, s, Ar), 7.98-7.91 (2H, m, Ar), 7.81-7.74 (3H, m, Ar),7.55 (2H, brt, J=7.0 Hz, Ar), 7.44 (1H, brt J=7.5 Hz, Ar), 4.31-4.24(2H, m, CH₂O), 3.61 (2H, t, J=5.0 Hz, CH₂N), 3.11 (3H, s, OMe).

Example 422-[4-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-Fluoro-5-nitrobenzoyl chloride

Prepared by the method of Example 15a), from 2-fluoro-5-nitrobenzolychloride (5 g, 0.03 mol) the subtitle compound was obtained. The productwas used directly in the next step without purification.

b) N-(2-Hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15b), from 2-amino-4-phenylphenol(5.55 g, 0.03 mol) and 2-fluoro-5-nitrobenzoyl chloride (7.0 g,0.035mol) the subtitle compound was obtained (11.0 g, 100%).

c) 2-(3-Nitro-6-fluorophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15c), fromN-(2-hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide (11.0 g, 0.03 mol)and p-toluenesulfonic acid monohydrate (11.88 g, 0.06 mol) the subtitlecompound was obtained (6 g, 58%). ¹H NMR (DMSO) δ 8.98(dd, 1H), 8.54(m,1H), 8.19(d, 1H), 7.97(d, 1H), 7.81(m, 4H), 7.52(t, 2H), 7.42(d, 1H).

d) 2-(3-Nitro-6-methoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 40a), from2-(3-nitro-6-fluorophenyl)-5-phenylbenzoxazole (500 mg, 1.5 mmol) andsodium methoxide (161 mg, 3.0 mmol) the subtitle compound was obtained(450 mg, 87%). ¹H NMR (DMSO) δ 8.88(c, 1H), 8.48(dd, 1H), 8.12(d, 1H),7.89(d, 1H), 7.75(m, 3H), 7.53(d, 1H), 7.50(t, 2H), 7.40 (d, 1H),4.11(s, 3H).

e) 2-(3-Amino-6-methoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from palladium (10 mol %) oncarbon and 2-(3-nitro-6-methoxyphenyl)-5-phenylbenzoxazole (450 mg, 1.3mmol) the subtitle compound was obtained (420 mg, 99%). The product wasused directly in the next step without purification.

f)2-[4-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-phenylbenzoxazole (420 mg, 1.42 mmol) and1,2,4-benzenetricarboxylic anhydride (273 mg, 1.42 mmol) the titlecompound was obtained, (460 mg, 66%). ¹H NMR (DMSO) δ 13.85(s, 1H),8.51(dd, 1H), 8.41(s, 1H), 8.29(d, 1H), 8.16(m, 2H), 7.95(d, 1H),7.81(m, 4H), 7.58(m, 2H), 7.54(d, 1H), 7.48(d, 1H), 4.12(s, 3H). MS 491m/z (M+H)⁺.

Example 432-[4Ethoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-ethoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 40a), from2-(5-nitro-2-fluorophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol) andsodium ethoxide (41 mg, 0.61 mmol) the subtitle compound was obtained(197 mg, 91%). ¹H NMR (DMSO) δ 8.92(d, 1H), 8.51(dd, 1H), 8.18(s, 1H),7.95(d, 1H), 7.83(d, 2H), 7.56(t, 3H), 7.47(t, 3H), 4.50(q, 2H), 1.57(t,3H).

b) 2-(5-Amino-2-ethoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15 e), from2-(5-nitro-2-ethoxyphenyl)-5-phenylbenzoxazole (197 mg, 0.55 mmol)thesubtitle compound was obtained (157 mg, 87%). MS 331 m/z (M+H)⁺.

c)2-[4-Ethoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-ethoxyphenyl)-5-phenylbenzoxazole (157 mg, 0.44 mmol) and1,2,4-benzenetricarboxylic anhydride (84 mg, 0.44 mmol) the titlecompound was obtained (133 mg, 60%). ¹H NMR (DMSO) δ 8.50(dd, 1H),8.40(s, 1H), 8.25(d, 1H), 8.17(m, 2H), 7.93(d, 1H), 7.80(m, 4H), 7.50(m,4H), 4.41(q, 2H), 1.52(t, 3H). MS 505 m/z (M+H)⁺.

Example 442-[4-(2-Methoxyethoxy)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-(2-methoxyethoxy)phenyl)-5-phenylbenzoxazole

Sodium hydride (30 mg, 1.2 mmol) was added portionwise to a stirredsuspension of 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg,0.6 mmol) in methoxyethanol (2 ml) at 0° C. When gas evolution hadvisibly ceased the mixture was allowed to warm to room temperature andthen heated at 55° C. for 3 h. After being allowed to cool to roomtemperature the mixture was diluted with water (5 ml) and extracted withEtOAc (3×5 ml). The combined organic extracts were washed with brine (5ml), dried (Na₂SO₄) and evaporated under reduced pressure to give thesubtitle compound (186 mg, 79%). ¹H NMR (DMSO) δ 8.90(d, 1H), 8.45(dd,1H), 8.10(d, 1H), 7.85(d, 1H), 7.77(m, 3H), 7.52(m, 3H), 7.41(t, 1H),4.50(t, 2H), 4.84(t, 2H), 3.40(s, 3H).

b) 2-(5-Amino-2-(2-methoxyethoxy)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-(2-methoxyethoxy)phenyl)-5-phenylbenzoxazole (186 mg, 0.48mmol) the subtitle compound was obtained (171 mg, 99%). MS 361 m/z

c)2-[4-(2Methoxyethoxy)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-(2-methoxyethoxy)phenyl)-5-phenylbenzoxazole (171 mg, 0.47mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) thetitle compound was obtained (141 mg, 56%). ¹H NMR (DMSO) δ 8.57(dd, 1H),8.46(s, 1H), 8.34(d, 1H), 8.24(d, 1H), 8.19(d, 1H), 7.97(d, 1H), 7.85(m,4H), 7.63(t, 3H), 7.53(t, 1H), 4.51(t, 2H), 3.95(t, 2H), 3.52(s, 3H). MS535 m/z (M+H)⁺.

Example 452-[4-Butoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-butoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) inbutanol (2 ml) the subtitle compound was obtained (195 mg, 87%). ¹H NMR(DMSO) δ 8.87(d, 1H), 8.45(dd, 1H), 8.08(d, 1H), 7.85(d, 1H), 7.70(m,3H), 7.51(t, 3H), 7.40(t, 1H), 4.35(t, 2H), 1.83(q, 2H), 1.57(m, 2H),1.01(t, 3H).

b) 2-(5-Amino-2-butoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-butoxyphenyl)-5-phenylbenzoxazole (195 mg, 0.50 mmol) thesubtitle compound was obtained (174 mg, 97%). MS 359 m/z (M+H)⁺.

c)2-[4-Butoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-butoxyphenyl)-5-phenylbenzoxazole (174 mg, 0.49 mmol) and1,2,4-benzenetricarboxylic anhydride (94 mg, 0.49 mmol) the titlecompound was obtained (146 mg, 56%). ¹H NMR (DMSO) δ 8.44(dd, 1H),8.32(s, 1H), 8.18(d, 1H), 8.12(d, 1H), 8.05(d, 1H), 7.82(d, 1H), 7.71(m,4H), 7.48(m, 3H), 7.39(t, 1H), 4.25(t, 2H), 1.83(m, 2H), 1.58(m,2H),1.00(t, 3H). MS 533 m/z (M+H)⁺.

Example 462-[4-Isopropoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-isopropoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) andisopropanol (2 ml) the subtitle compound was obtained (204 mg, 84%). ¹HNMR (DMSO) δ 8.85(d, 1H), 8.44(dd, 1H), 8.12(d, 1H), 7.90(d, 1H),7.76(m, 3H), 7.54(m, 3H), 7.40(t, 1H), 4.35(m, 1H), 1.45(d, 6H).

b) 2-(5-Amino-2-isopropoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-isopropylphenyl)-5-phenylbenzoxazole (204 mg, 0.54 mmol)the subtitle compound was obtained (188 mg, 100%). MS 345 m/z (M+H)⁺.

c)2-[4-Isopropoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-isopropylphenyl)-5-phenylbenzoxazole (188 mg, 0.55 mmol)and 1,2,4-benzenetricarboxylic anhydride (106 mg, 0.55 mmol) the titlecompound was obtained (102 mg, 36%). ¹H NMR (DMSO) δ 8.42(dd, 1H),8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H),7.85(d, 1H), 7.71(m, 3H), 7.50(m,3H),7.39(t, 1H), 4.87(m, 1H), 1.41(d, 6H). MS 519 m/z (M+H)⁺.

Example 472-[4-Allyloxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-allyloxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) andallyl alcohol (4 ml) the subtitle compound was obtained (216 mg, 97%).¹H NMR (DMSO) δ 8.83(d, 1H), 8.38(dd, 1H), 8.06(d, 1H), 7.82(d, 1H),7.69(m, 3H), 7.44(t, 3H), 7.33(t, 1H), 6.08(m, 1H), 5.60(dd, 1),5.30(dd, 1H), 4.90(m, 2H).

b) 2-(5-Amino-2-allyloxyphenyl)-5-phenylbenzoxazole

Powdered zinc (377 mg, 5.8 mmol) was added to a solution of2-(5-nitro-2-allyloxyphenyl)-5-phenylbenzoxazole (216 mg, 0.58 mmol) inacetic acid (2 ml). After 2 h the reaction mixture was filtered throughcelite and the filtrate concentrated. The residue was dissolved in ethylacetate (10 ml) and washed with saturated sodium hydrogen carbonatesolution (2×25 ml). The organic layer was dried over sodium sulfate andconcentrated to give the subtitle compound (342 mg, 100%). The productwas used directly in the next step without purification.

c)2-[4-Allyloxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-allyloxyphenyl)-5-phenylbenzoxazole (190 mg, 0.55 mmol) and1,2,4-benzenetricarboxylic anhydride (106 mg, 0.55 mmol) the titlecompound was obtained (102 mg, 36%). ¹H NMR (DMSO) δ 8.57(m, 1H),8.35(dd, 1H), 8.37(s, 1H), 8.13(d, 1H), 7.94(m, 3H), 7.77(d, 1H),7.63(m, 3H), 7.35(m, 4H), 6.04(m,1H), 5.49(dd, 1H), 5.33(dd, 1H),4.77(d, 2H). MS 517 m/z (M+H)⁺.

Example 482-[4-Hydroxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (400 mg, 1.2 mmol) in3-furanmethanol (2 ml) the subtitle compound was obtained (392 mg, 79%).The product was used directly in the next step without purification.

b) 2-(5-Amino-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 47b), from2-(5-nitro-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole (392 mg, 0.95mmol) and zinc (622 mg, 9.5 mmol) the subtitle compound was obtained(382 mg, 93%). The product was used directly in the next step withoutpurification.

c)2-[4-Hydroxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole (144 mg, 0.28mmol) and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) thetitle compound was obtained (100 mg, 55%). ¹H NMR (DMSO) δ 8.48(dd, 1H),8.39(s, 1H), 8.25(d, 1H), 8.21(d, 1H), 8.17(d, 11), 8.00(d, 1H), 7.82(m,3H), 7.70(dd, 1H), 7.57(t,2H), 7.46(t, 1H), 7.38(d, 1H). MS 477 m/z(M+H)⁺.

Example 492-[4-Propoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-propoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (400 mg, 1.2 mmol) inpropanol (2 ml) the subtitle compound was obtained (325 mg, 73%). MS 375m/z (M+H)⁺.

b) 2-(5-Amino-2-propoxyphenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-propoxyphenyl)-5-phenylbenzoxazole (325 mg, 0.89 mmol) thesubtitle compound was obtained (264 mg, 88%). MS 345 m/z (M+H)⁺.

c)2-[4-Propoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-nitro-2-propoxyphenyl)-5-phenylbenzoxazole (125 mg, 0.36 mmol) and1,2,4-benzenetricarboxylic anhydride (68 mg, 0.36 mmol) the titlecompound was obtained (37 mg, 21%). ¹H NMR (DMSO) δ 8.47(d, 1H), 8.38(s,1H), 8.25(d, 1H), 8.13(m, 2H), 7.89(d, 1H), 7.76(m, 4H), 7.49(m, 4H),4.27(t, 2H), 1.92(m, 2H), 1.15(t, 3H). MS 519 m/z (M+H)⁺.

Example 502-[2-(3-Furanylmethoxy)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4(3-furanylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(3-nitro-4-fluorophenyl)-5-phenylbenzoxazole (0.70 g, 3.0 mmol) and3-furanmethanol (3.0 ml) the subtitle compound was obtained (0.78 g(90%). ¹H NMR (DMSO) δ 8.63(d, 1H), 8.44(dd, 1H), 8.06(d, 1H), 7.87(m,2H), 7.76-7.71(m, 5H), 7.50(m, 2H), 7.39(t, 1H), 6.60(d, 1H), 5.32(s,2H).

b) 2-(3-Amino-4(3-furanylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 40b), from2-(3-nitro-4-(3-furanylmethoxy)-5-phenylbenzoxazole (0.78 g, 1.9 mmol)the subtitle compound was obtained (0.40 g, 56%). ¹H NMR (DMSO) δ7.94(d, 1H), 7.70-7.46(m, 10H), 7.38(t, 1H), 7.01(d, 1H), 6.55(s, 1H),5.08(s, 2H).

c)2-[2-(3-Furanylmethoxy)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-(3-furanylmethoxy)-5-phenylbenzoxazole (200 mg, 0.52 mmol)and 1,2,4-benzenetricarboxylic anhydride (10 mg, 0.52 mmol) the titlecompound was obtained (149 mg, 51%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.34(m, 3H), 8.13(d, 1H), 8.03(d, 1H), 7.84(d, 1H), 7.75-7.69(m, 4H),7.58(m, 2H), 7.49(m, 2H), 7.39(t, 2H), 6.41(d, 1H), 5.18(s, 2H). MS555.4 m/z (M−H)⁻.

Example 51 c)2-[4-(2Methoxyethoxy)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-(2-methoxyethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from methoxyethanol (2.0 ml) and2-(3-nitro-4-fluorophenyl)-5-phenylbenzoxazole (0.20 g, 3.0 mmol) thesubtitle compound was obtained (0.23 g (99%). ¹H NMR (CDCl₃) δ 8.61(d,1H), 8.41(dd, 1H), 8.05(d, 1H), 7.86(d, 1H), 7.75-7.70(m, 3H), 7.62(d,1H), 7.50(m, 2H), 7.39(t, 1H), 4.42(t, 2H), 3.72(t, 2H), 3.33(s, 3H).

b) 2-(3-Amino-4-(2-methoxyethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 40b), from2-[3-nitro-4-(2-methoxyethoxy)]-5-phenylbenzoxazole (0.10 g, (1.9 mmol)the subtitle compound was obtained (0.60 g, 65%). ¹H NMR (CDCl₃) δ7.93(d, 1H), 7.67-7.53(m, 6H), 7.48(m, 2H), 7.37(t, 1H), 6.93(d, 1H),4.26(t, 2H), 3.82(t, 2H), 3.48(s, 3H).

c)2-[2-(2-Methoxyethoxy)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-(2-methoxyethoxy)-5-phenylbenzoxazole (48 mg, 0.13 mmol)and 1,2,4-benzenetricarboxylic anhydride (25 mg, 0.13 mmol) the titlecompound was obtained (30 mg, 42%). ¹H NMR (CDCl₃) δ 8.68(s, 1H),8.56(d, 1H), 8.36-8.30(m, 2H), 8.12-8.06(m, 2H), 7.68-7.62(m, 4H),7.49(m, 2H), 7.39(t, 1H), 7.24(m, 1H), 4.28(t, 2H), 3.70(t, 2H), 3.31(s,3H). MS 533.1 m/z (M−H)⁻.

Example 522-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-tetrahydrofuranylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-(3-tetrahydrofuranylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(3-nitro-4-fluoro)-5-phenylbenzoxazole (200 mg, 0.6 mmol) andtetrahydro-3-furanmethanol (1.221 g, 11.69 mmol) the subtitle compoundwas obtained (220 mg, 88%). ¹H NMR (DMSO) δ 8.61(d, 1H), 8.41(dd, 1H),8.04(d, 1H), 7.85(d, 1H), 7.27(m, 3H), 7.60(d, 1H), 7.50(m, 2H), 7.40(t,1H), 4.23(m, 2H), 3.79(m, 2H), 3.67(m, 1H), 3.57(m, 1H), 2.70(m, 1H),2.03(m, 1H), 1.70(m, 1H).

b) 2-(3-Amino-4-(3-tetrahydrofuranylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-4-(3-tetrahydrofuranylmethoxy)-5-phenylbenzoxazole (150 mg,0.36 mmol) and powdered zinc (235 mg, 3.6 mmol) the subtitle compoundwas obtained (115 mg, 83%). ¹H NMR (DMSO) δ 7.98(d, 1H), 7.79(d, 1H),7.73(m, 2H), 7.65(dd, 1H), 7.54-7.36(m, 5H), 7.02(d, 1H), 4.01(m, 2H),3.88-3.76(m, 2H), 3.68(m, 1H), 3.59(m, 1H), 2.71(m, 1H), 2.07(m, 1H),1.70(m, 1H).

c)2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-tetrahydrofuranylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-(3-tetrahydrofuranylmethoxy)-5-phenylbenzoxazole (50 mg,0.13 mmol) and 1,2,4-benzenetricarboxylic anhydride (25 mg, 0.13 mmol)the title compound was obtained (20 mg, 28%). ¹H NMR (DMSO) δ 8.46(dd,1H), 8.35(m, 3H), 8.14(dd, 1H), 8.03(d, 1H), 7.85(d, 1H), 7.72(m, 3H),7.50(m, 3H), 7.39(t, 1H), 4.10(m, 2H), 3.56(m, 3H), 3.52(m, 2H), 1.85(m,1H), 1.54(m, 1H). MS 559.0 m/z (M−H)⁻.

Example 532-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thiophenylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-(3-thiophenylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 44a), from2-(3-nitro-4-fluorophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) and3-thiophenemethanol (1.36 g, 12 mmol) the subtitle compound was obtained(202 mg, 79%). ¹H NMR (DMSO) δ 8.64(d, 1H), 8.43(dd, 1H), 8.05(d, 1H),7.86(d, 1H), 7.73(m, 4H), 7.62(m, 2H), 7.49(m, 2H), 7.39(t, 1H),7.21(dd, 1H), 5.44(s, 2H).

b) 2-(3-Amino-4-(3-thiophenylmethoxy)-5-phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-4-thiophen-3-ylmethoxyphenyl)-5-phenylbenzoxazole (150 mg,0.35 mmol) the subtitle compound was obtained (84 mg, 60%). ¹H NMR(DMSO) δ 7.99(s, 1H), 7.81-7.32(m, 11H), 7.24(d, 1H), 7.09(d, 1H),5.22(s, 2H).

c)2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thiophenylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-(3-thiophenylmethoxy)-5-phenylbenzoxazole (50 mg, 0.13mmol) and 1,2,4-benzenetricarboxylic anhydride (25 mg, 0.13 mmol) thetitle compound was obtained (34 mg, 47%). ¹H NMR (DMSO) δ 8.45(dd, 1H),8.34(m, 3H), 8.14(d, 1H), 8.03(d, 1H), 7.84(d, 1H), 7.73(m, 3H),7.56-7.47(m, 5H), 7.39(t, 1H), 7.04(dd, 1H), 531(s, 2H). MS 570.9 m/z(M−H)⁻.

Example 542-[2-(4-Morpholinyl)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid, acetic acid salt a) 2-(3-Nitro-4-morpholinyl)-5-phenylbenzoxazole

Morpholine (2.0 ml) was added dropwise to a solution of2-(3-nitro-4-fluorophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) in THF(10 ml). After 4 h the reaction was concentrated. The residue wastriturated with methanol and filtered to give the subtitle compound (216mg, 90%). ¹H NMR (CDCl₃) δ 8.69(d, 1H), 8.03(dd, 1H), 7.95(d, 1H),7.65-7.58(m, 4H), 7.48(m, 2H), 7.34(t, 1H), 7.22(d, 1H), 3.89(t, 4H),3.21(t, 4H).

b) 2-(3-Amino-4-morpholinyl)-5-phenylbenzoxazole

Prepared by the method of Example 40b), from2-(3-nitro-4-morpholinyl)-5-phenylbenzoxazole (100 mg, 0.25 mmol) thesubtitle compound was obtained (69 mg, 74%). ¹H NMR (CDCl₃) δ 7.94(d,1H), 7.70-7.54(m, 6H), 7.48(m, 2H), 7.38(t, 1H), 7.11(d, 1H), 3.90(t,4H), 3.03(t, 4H).

c)2-[2-(4-Morpholinyl)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid, acetic acid salt

Prepared by the method of Example 15f), from2-(3-amino-4-morpholinyl)-5-phenylbenzoxazole (47 mg, 0.12 mmol) and1,2,4-benzenetricarboxylic anhydride (24 mg, 0.12 mmol) the titlecompound was obtained (20 mg, 29%). ¹H NMR (DMSO) δ 8.46(dd, 1H),8.36(d, 1H), 8.28(m, 2H), 8.14(d, 1H), 8.02(d, 1H), 7.72(m, 3H), 7.50(m,2H), 7.39(t, 1H), 3.48(t, 4H), 2.93(t, 4H), 1.91(s, 3H). MS 544.0 m/z(M−H)⁻.

Example 552-[4-Ethylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-ethylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andethylamine (3 ml) the subtitle compound was obtained (217 mg, 100%). MS360 m/z (M+H)⁺.

b) 2-(5-Amino-2-ethylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-ethylaminophenyl)-5-phenylbenzoxazole (217 mg, 0.60 mmol)the subtitle compound was obtained (158 mg, 80%). The product was useddirectly in the next step without purification.

c)2-[4-Ethylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-ethylaminophenyl)-5-phenylbenzoxazole (158 mg, 0.48 mmol)and 1,2,4-benzenetricarboxylic anhydride (92 mg, 0.48 mmol) the titlecompound was obtained (154 mg, 64%). ¹H NMR (DMSO) δ 8.42(m, 2H),8.31(s, 1H), 8.14(d, 1H), 8.07(m, 2H), 7.83(d, 1H), 7.74(m, 3H), 7.50(m,3H), 7.39(t, 1H), 7.04(d, 1H), 3.48(q, 2H), 1.39(t, 3H). MS 504 m/z(M+H)⁺.

Example 562-[4-Propylamino-3-(5-phenylbenzoxazol-2-y))phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-propylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitro)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andpropylamine (3 ml) the subtitle compound was obtained (228 mg, 100%). MS374 m/z (M+H)⁺.

b) 2-(5-Amino-2-propylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-propylaminophenyl)-5-phenylbenzoxazole (228 mg; 0.61 mmol)the subtitle compound was obtained (161 mg, 77%). The product was useddirectly in the next step without purification.

c)2-[4-Propylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-propylaminophenyl)-5-phenylbenzoxazole (161 mg, 0.47 mmol)and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) the titlecompound was obtained (174 mg, 72%). ¹H NMR (DMSO) δ 8.51(t, 1H),8.42(dd, 1H), 8.31(s, 1H), 8.15(d, 1H), 8.08(m, 2H), 7.77(m, 4H),7.50(m, 3H), 7.39(t, 1H), 7.03(d, 1H), 3.40(q, 2H), 1.68(m, 2H), 1.34(t,3H). MS 518 m/z (M+H)⁺.

Example 572-[4-(2-Methoxyethylamino)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-(2methoxyethylamino)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and2-methoxyethylamine (3 ml) the subtitle compound was obtained (216 mg,93%). MS 390 m/z (M+H)⁺.

b) 2-(5-Amino-2-(2-methoxyethylamino)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-(2-methoxyethylamino)phenyl)-5-phenylbenzoxazole (216 mg,0.55 mmol) the subtitle compound was obtained (131 mg, 67%). The productwas used directly in the next step without purification.

c)2-[4-(2-Methoxyethylamino)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-(2-methoxyethylamino)phenyl)-5-phenylbenzoxazole (131 mg,0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg, 0.36 mmol)the title compound was obtained (138 mg, 72%). ¹H NMR (DMSO) δ 8.61(t,1H), 8.42(dd, 1H), 8.31(s, 1H), 8.13(d, 1H), 8.08(m, 2H), 7.83(d, 1H),7.53(m, 3H), 7.50(m, 3H), 7.41(t, 1H), 7.08(d, 1H), 3.69(m, 2H), 3.59(m,2H), 3.35(s, 3H). MS 534 m/z (M+H)⁺.

Example 582-[4-Morpholinyl-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2(5-Nitro-2-(4-morpholinyl)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andmorpholine (3 ml) the subtitle compound was obtained (274 mg, 100%). MS402 m/z (M+H)⁺.

b) 2-(5-Amino-2-(4-morpholinyl)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-(4-morpholinyl)phenyl)-5-phenyl benzoxazole (274 mg, 0.68mmol) the subtitle compound was obtained (175 mg, 69%). The product wasused directly in the next step without purification.

c)2-[4-Morpholinyl-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-(4-morpholinyl)phenyl)-5-phenylbenzoxazole (175 mg, 0.47mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) thetitle compound was obtained (136 mg, 53%). ¹H NMR (DMSO) δ 8.43(dd, 1H),8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H), 7.90(d, 1H), 7.75(m, 3H),7.65(dd, 1H), 7.50(t, 2H), 7.38(m, 2H), 3.80(m, 4H), 3.05(m, 4H). MS 546m/z (M+H)⁺.

Example 592-[4-Butylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-butylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andbutylamine (2 ml) the subtitle compound was obtained (563 mg, 100%). MS388 m/z (M+H)⁺.

b) 2-(5-Amino-2-butylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-butylaminophenyl)-5-phenylbenzoxazole (563 mg, 1.50 mmol)the subtitle compound was obtained (409 mg, 76%). MS 358 m/z (M+H)⁺.

c)2-[4-Butylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-butylaminophenyl)-5-phenylbenzoxazole (409 mg, 1.14 mmol)and 1,2,4-benzenetricarboxylic anhydride (219 mg, 1.14 mmol) the titlecompound was obtained (390 mg, 64%). ¹H NMR (DMSO) δ 8.71(t, 1H),8.65(dd, 1H), 8.36(d, 1H), 8.29(m, 2H), 8.08(d, 1H), 8.00(d, 2H),7.93(dd, 1H), 7.73(m, 3H) 7.62(t, 1H), 7.27(d, 1H), 3.60(m, 2H), 1.97(q,2H), 1.74(m, 2H), 1.22(t, 3H) MS 532 m/z (M+H)⁺.

Example 602-[4-Hexylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-hexylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andhexylamine (2 ml) the subtitle compound was obtained (298 mg, 100%). MS416 m/z (M+H)⁺.

b) 2-(5-Amino-2-hexyl amino phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-hexylaminophenyl)-5-phenylbenzoxazole (289 mg, 0.69 mmol)the subtitle compound was obtained (237 mg, 89%). MS 386 m/z

c)2-[4-Hexylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-hexylaminophenyl)-5-phenylbenzoxazole (237 mg, 0.61 mmol)and 1,2,4-benzenetricarboxylic anhydride (117 mg, 0.61 mmol) the titlecompound was obtained (129 mg, 38%). ¹H NMR (DMSO) δ 8.46(m, 2H),8.30(m, 1H), 8.08(m, 2H), 7.80(m, 4H), 7.49(m, 3H), 7.40(m, 1H), 7.02(m,1H), 3.40 (m, 2H), 1.75(m, 2H), 1.41(m, 6H), 0.91(m, 3H). MS 560 m/z(M+H)⁺.

Example 612-[4-Pentylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro1H-isoindole-5-carboxylicacid a) 2-(5-Nitro-2-pentylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), andpentylamine (2 ml) the subtitle compound was obtained (289 mg, 100%). MS402 m/z (M+H)⁺.

b) 2-(5-Amino-2-pentylaminophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(5-nitro-2-pentylaminophenyl)-5-phenylbenzoxazole (289 mg, 0.72 mmol)the subtitle compound was obtained (239 mg, 90%). MS 372 m/z (M+H)⁺.

c)2-[4-Pentylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(5-amino-2-pentylaminophenyl)-5-phenylbenzoxazole (239 mg, 0.64 mmol)and 1,2,4-benzenetricarboxylic anhydride (123 mg, 0.64 mmol) the titlecompound was obtained (114 mg, 33%). ¹H NMR (DMSO) δ 8.48(t, 1H),8.43(dd, 1H), 8.30(s, 1H), 8.14(d, 1H), 8.07(m, 2H), 7.83(d, 1H),7.74(m, 3H), 7.48(m, 3H), 7.39(t, 1H), 7.02(d, 1H), 3.50 (m, 2H),1.75(q, 2H), 1.43(m, 4H), 0.95(t, 3H). MS 546 m/z (M+H)⁺.

Example 622-(3-Benzoxazol-2-yl-4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-Fluoro-5-nitrobenzoylchloride

Prepared by then method of Example 15a), from 2-fluoro-5-nitrobenzoicacid (2.0 g, 11.0 mmol) and oxalyl chloride (2.89 ml, 33.0 mmol) thesubtitle compound was obtained. The product was used directly in thenext step without purification.

b) N-Phenyl-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15b), from2-fluoro-5-nitrobenzoylchloride (2.23 g, 11.0 mmol) and 2-aminophenol(1.20 g, 11.0 mmol) the subtitle compound was obtained (2.89 g, 91%). ¹HNMR (DMSO) δ 10.00(s, 1H), 9.75(d, 1H), 8.62(m, 1H), 8.46(m, 1H),7.96(d, 1H), 7.67(t, 1H), 7.03(t, 1H), 6.94(d, 1H), 6.85(t, 1H).

c) 2-(3-Nitro-6-fluorophenyl)benzoxazole

Prepared by the method of Example 15c), fromN-phenyl-2-fluoro-5-nitrobenzamide (2.89 g, 10.4 mmol) andp-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol) the subtitlecompound was obtained (2.41 g, 90%). ¹H NMR (DMSO) δ 8.95(m, 1H),8.52(m, 1H), 7.90(m, 2H), 7.81(t, 1H), 7.50(m, 2H).

d) 2-(3-Nitro-6-propylamino)benzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)benzoxazole (500 mg, 1.93 mmol) andpropylamine (228 μL, 3.87 mmol) the subtitle compound was obtained (500mg, 87%). ¹H NMR (DMSO) δ 9.21(t, 1H), 8.81(d, 1H), 8.20(dd, 1H),7.83(m, 2H), 7.46(m, 2H), 7.03(d, 1H), 3.44(q, 2H), 1.74(m, 2H), 1.04(t,3H).

e) 2-(3-Amino-6-propylamino)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)benzoxazole (500 mg, 1.68 mmol) thesubtitle compound was prepared (375 mg, 83%). ¹H NMR (DMSO) δ 7.73(m,2H), 7.59(t, 1), 7.39-7.33(m, 3H), 6.82(dd, 1H), 6.69(d, 1H), 4.59(bs,2H), 3.20(q, 2H), 1.67(m, 2H), 1.01(t, 3H).

f)2-(3-Benzoxazol-2-yl-4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylamino)benzoxazole (100 mg, 0.37 mmol) and1,2,4-benzenetricarboxylic anhydride (79 mg, 0.41 mmol) the titlecompound was obtained (89 mg, 54%). ¹H NMR (DMSO) δ 8.48(m, 2H), 8.30(s,1H), 8.11(d, 1H), 8.06(d, 1H), 7.83-7.74(m, 2H), 7.49-7.40(m, 3H),7.03(d, 1H), 3.37(q, 2H), 1.75(m, 2H), 1.06(t, 3H). MS 440.2 m/z (M−H)⁻.

Example 632-(3-Naphtho[2,3-d]oxazol-2-yl4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-fluorophenyl)naphthol

Prepared by the method of Example 15a), from 3-amino-2-naphthol (781 mg,4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol) thesubtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenylnaphth[2,3-d]oxazole

Prepared by the method of Example 15b), from2-(3-nitro-6-fluorophenyl)naphthol (800 mg, 2.8 mmol) andp-toluenesulfonic acid monohydrate (1.17 g, 6.16 mmol) the subtitlecompound was obtained (403 mg, 53%). MS m/z 309.2 (M+H)⁺.

c) 2-(3-Nitro-6-propylaminophenyl)naphth[2,3-d]oxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)naphth[2,3-d]oxazole (277 mg, 0.9 mmol) andpropylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (250mg, 80%). ¹H NMR (DMSO) δ 9.37(t, 1H), 8.90(d, 1H), 8.38(s, 1H), 8.33(s,1H), 8.26(dd, 1H), 8.11(m, 2H), 7.56(m, 1H), 7.11(d, 1H), 3.50(q, 2H),1.76(m, 2H), 1.09(t, 3H).

d) 2(3-Amino-6-propylaminophenyl)naphth[2,3-d]oxazole

Prepared by the method of Example 15e),2-(3-nitro-6-propylaminophenyl)naphth[2,3-d]oxazole (250 mg, 0.7 mmol)the subtitle compound was obtained (188 mg, 85%). MS 315.1 (M−H)⁻.

e)2-(3-Naphtho[2,3-d]oxazol-2-yl-4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)naphth[2,3-d]oxazole (100 mg, 0.32 mmol)and 1,2,4-benzenetricarboxylic anhydride (67 mg, 0.35 mmol) the titlecompound was obtained (97 mg, 62%). ¹H NMR (DMSO) δ 8.61(t, 1H),8.42(dd, 1H), 8.32(m, 2H), 8.19(m, 2H), 8.11-8.05(m, 3H), 7.51(m, 3H),7.05(d, 1H), 3.39(q, 2H), 1.79(m, 2H), 1.10(t, 3H). MS 490.0 m/z (M−H)⁻.

Example 642-[3-(5-Chlorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-chlorophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4-chlorophenol (705mg, 4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-chlorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-chlorophenyl)-2-fluoro-5-nitrobenzamide (800 mg, 2.6mmol) and p-toluenesulfonic acid monohydrate (1.17 g, 6.16 mmol) thesubtitle compound was obtained (403 mg, 53%). MS m/z 291.9 (M+H)⁺.

c) 2-(3-Nitro-6-propylaminophenyl)-5-chlorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-chlorobenzoxazole (263 mg, 0.9 mmol) andpropylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (296mg, 99%). ¹H NMR (DMSO) δ 9.33(t, 1H), 9.02(s, 1H), 8.44(dd, 1H),8.16-8.11(m, 2H), 7.75(dd, 1H), 7.29(d, 1H), 3.67(q, 2H), 1.97(m, 2H),1.28(t, 3H).

d) 2-(3-Amino-6-propylaminophenyl)-5-chlorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-chlorobenzoxazole (250 mg, 0.75 mmol)the subtitle compound was obtained (203 mg, 90%). MS m/z 299.0 (M−H)⁻.

e)2-[3-(5-Chlorobenzoxazol-2-yl)-4propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-chlorobenzoxazole (100 mg, 0.33 mmol)and 1,2,4-benzenetricarboxylic anhydride (69 mg, 0.36 mmol) the titlecompound was obtained (92 mg, 58%). ¹H NMR (DMSO) δ 8.41(dd, 1H),8.37(t, 1H), 8.09-8.05(m, 2H), 7.92(d, 1H), 7.79(d, 1H), 7.47(m, 2H),7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS m/z 474.0 (M−H)⁻.

Example 652-[3-(6-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-4-methylphenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-5-methylphenol (605mg, 4.9 mmol) and 2-fluoro-5-nitrobenzoyl chloride (1.00 g, 5.0 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-6-methylbenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-4-methylphenyl)-2-fluoro-5-nitrobenzamide (300 mg, 2.8mmol) and p-toluenesulfonic acid monohydrate (1.17 g, 6.16 mmol) thesubtitle compound was obtained (403 mg, 53%). MS m/z 273.2 (M+H)⁺.

c) 2-(3-Nitro-4-propylaminophenyl)-6-methylbenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-6-methylbenzoxazole (250 mg, 0.9 mmol) andpropylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (262mg, 94%). ¹H NMR (DMSO) δ 9.21(t, 1H), 8.78(d, 1H), 8.19(dd, 1H),7.70-7.66(m, 2H), 7.25(d, 1H), 7.03(d, 1H), 3.43(q, 2H), 2.47(s, 3H),1.73(m, 2H), 1.01(t, 3H).

d) 2-(3-Amino-6-propylaminophenyl)-6-methylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-6-methylbenzoxazole (250 mg, 0.8 mmol)the subtitle compound was obtained (205 mg, 91%). MS m/z 279.1 (M−H)⁻.The product was used directly in the next step without purification.

e)2-[3-(6-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-6-methylbenzoxazole (100 mg, 0.33 mmol)and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) the titlecompound was obtained (87 mg, 58%). ¹H NMR (DMSO) δ 8.47-8.40(m, 2H),8.30(s, 1H), 8.08-8.06(m, 2H), 7.68(d, 1H), 7.56(s, 1H), 7.44(dd, 1H),7.23(d, 1H), 7.01(d, 1H), 3.34(m, 2H), 2.46(s, 3H), 1.74(m, 2H), 1.05(t,3H). MS 454.1 m/z (M−H)⁻.

Example 662-[3-(6-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-4-fluorophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-5-fluorophenol (508mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 g, 4.0 mmol) thesubtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-6-fluorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-4-fluoro)-2-fluoro-5-nitrobenzamide (1.18 g, 4.0 mmol) andp-toluenesulfonic acid monohydrate (1.67 g, 8.8 mmol) the subtitlecompound was obtained (675 mg, 61%). MS m/z 277.1 (M+H)⁺.

c) 2-(3-Nitro-6-propylaminophenyl)-6-fluorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-6-fluorobenzoxazole (552 mg, 2.0 mmol) andpropylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-6-fluorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-4-fluorobenzoxazole (205 mg, 0.65 mmol)the subtitle compound was obtained (178 mg, 96%). MS 286.3 m/z (M+H)⁺.

e)2-[3-(6-Fluorobenzoxazol-2-yl)-4propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-6-fluorobenzoxazole (71 mg, 0.25 mmol)and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the titlecompound was obtained (84 mg, 73%). ¹H NMR (DMSO) δ 8.41(dd, 1H),8.36(t, 1H), 8.30(s, 1H), 8.07(m, 2H), 7.84(m, 1H), 7.77(dd, 1H),7.46(dd, 1H), 7.29(m, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H),1.05(t, 3H). MS 458.1 m/z (M−H)⁻.

Example 672-[3-(5-Bromobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4-bromophenol (752mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 g, 4.0 mmol) thesubtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-bromobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide (1.42 g, 4.0 mmol)and p-toluenesulfonic acid monohydrate (1.67 g, 8.8 mmol) the subtitlecompound was obtained (654 mg, 48%). MS 339.0 m/z (M+H)⁺.

c) 2-(3-Nitro-6-propylaminophenyl)-5-bromobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-bromobenzoxazole (576 mg, 2.0 mmol) andpropylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-5-bromobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (244 mg, 0.65 mmol)the subtitle compound was obtained (217 mg, 96%). MS 346.2 & 348.2 m/z(M+H)⁺.

e)2-[3-(5-Bromobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-bromobenzoxazole (87 mg, 0.25 mmol)and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the titlecompound was obtained (77 mg, 59%). ¹H NMR (DMSO) δ 8.41(dd, 1H),8.37(t, 1H), 8.30(s, 1H), 8.09-8.05(m, 3.H), 7.74(d, 1H), 7,57(dd, 1H),7.48(dd, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS518.0 m/z (M−H)⁻.

Example 682-[3-(5-Methoxybenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-methoxyphenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4-methoxyphenol(557 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 mg, 4.0mmol) the subtitle compound was obtained. The product was used directlyin the next step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-methoxybenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-methoxyphenyl)-2-fluoro-5-nitro benzamide (1.23 g, 4.0mmol) and p-toluenesulfonic acid monohydrate (1.67 g, 8.8 mmol) thesubtitle compound was obtained (700 mg, 53%). MS 289.1 m/z (M+H)⁺.

c) 2-(3-Nitro-6-propylaminophenyl)-5-methoxybenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-methoxybenzoxazole (674 mg, 2.0 mmol) andpropylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-5-methoxybenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-methoxybenzoxazole (213 mg, 0.65 mmol)the subtitle compound was obtained (178 mg, 92%). MS 298.3 m/z (M+H)⁺.

e)2-[3-(5-Methoxybenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-methoxybenzoxazole (74 mg, 0.25 mmol)and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the titlecompound was obtained (68 mg, 58%). ¹H NMR (DMSO) δ 8.46(t, 1H),8.41(dd, 1H), 8.22 (s, 1H), 8.07(m, 2H), 7.64(d, 1H), 7.45(dd, 1H),7.37(d, 1H), 7.00(m, 2H), 3.84(s, 3H), 3.34(m, 2H), 1.75(m, 2H), 1.06(t,3H). MS 470.1 m/z (M−H)⁻.

Example 692-[3-(5,7-Dichlorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-3,5-dichlorophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4,6-dichlorophenol(409 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3mmol) the subtitle compound was obtained. The product was used directlyin the next step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5,7-dichlorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-3,5-dichlorophenyl)-2-fluoro-5-nitrobenzamide (798 g, 2.3mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (597 mg, 79%). ¹H NMR (DMSO) δ 9.00(t,1H), 8.78(s, 1H), 8.24(dd, 1H), 7.97(s, 1H), 7.77(s, 1H), 7.09(d, 1H),3.46(q, 2H), 1.73(m, 2H), 1.04(t, 3H).

c) 2-(3-Nitro-6-propylaminophenyl)-5,7-dichlorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5,7-dichlorobenzoxazole (250 mg, 0.8 mmol)and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained.The product was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-5,7-dichlorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-propylaminophenyl)-5,7-dichlorobenzoxazole (150 mg, 0.4 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

e)2-[3-(5,7-Dichlorobenzoxazol-2-yl)-4-propylaminophenyl]-3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-propylaminophenyl)-5,7-dichlorobenzoxazole (134 mg, 0.4 mmol)and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the titlecompound was obtained (127 mg, 62%). ¹H NMR (DMSO) δ 8.41(dd, 1H),8.29(m, 2H), 8.10(d, 1H), 8.06(d, 1H), 7.94(d, 1H), 7.68(d, 1H),7.49(dd, 1H), 7.05(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS509.9 m/z (M−H)⁻.

Example 702-[3-(5-Trifluoromethylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-trifluoromethylphenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from2-amino-4-trifluoromethylphenol (407 mg, 2.3 mmol) and2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitlecompound was obtained. The product was used directly in the next stepwithout purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-trifluoromethylbenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-trifluoromethylphenyl)-2-fluoro-5-nitrobenzamide (667 g,2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (349 mg, 56%). ¹H NMR (DMSO) δ 8.95(m,1H), 8.56(m, 1H), 8.36(s, 1H), 8.12(d, 1H), 7.84(m, 2H).

c) 2-(3-Nitro-6-propylaminophenyl)-5-trifluoromethylbenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-trifluoromethylbenzoxazole (218 mg, 0.8mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound wasobtained. The product was used directly in the next step withoutpurification.

d) 2-(3-Amino-6-propylaminophenyl)-5-trifluoromethylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-trifluoromethylbenzoxazole (124 mg,0.4 mmol) the subtitle compound was obtained. The product was useddirectly in the next step without purification.

e)2-[3-(5-Trifluoromethylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-trifluoromethylbenzoxazole (113 mg,0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) thetitle compound was obtained (120 mg, 59%). ¹H NMR (DMSO) δ 8.41(m, 2H),8.30(s, 1H), 8.23(s, 1H), 8.12(d, 1H), 8.07(d, 1H), 7.97(d, 1H), 7.77(d,1H), 7.49(dd, 1H), 7.04 (d, 1H), 3.34(m, 2H) 1.75(m, 2H), 1.06(t, 3H).MS 507.7 m/z (M−H)⁻.

Example 712-[3-(5-Bromo-7-fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-3-fluoro-5-bromophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from2-amino-4-bromo-6-fluorophenol (473 mg, 2.3 mmol) and2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitlecompound was obtained. The product was used directly in the next stepwithout purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-bromo-7-fluorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-3-fluoro-5-bromophenyl)-2-fluoro-5-nitrobenzamide (858 mg,2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (475 mg, 58%). ¹H NMR (DMSO) δ 8.91(m,1H), 8.57(m, 1H), 8.06(s, 1H), 7.81(m, 3H).

c) 2-(3-Nitro-6-propylaminophenyl)-5-bromo-7-fluorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-bromo-7-fluorobenzoxazole (284 mg, 0.8mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound wasobtained. The product was used directly in the next step withoutpurification.

d) 2-(3-Amino-6-propylaminophenyl)-5-bromo-7-fluorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-bromo-7-fluorobenzoxazole (158 mg, 0.4mmol) the subtitle compound was obtained. The product was used directlyin the next step without purification.

e)2-[3-(5-Bromo-7-fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-trifluoromethylbenzoxazole (146 mg,0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) thetitle compound was obtained (127 mg, 59%). ¹H NMR (DMSO) δ 8.41(d, 1H),8.28(m,2H), 8.12(d, 1H), 8.06(d, 1H), 7.94(s, 1H), 7.68(d, 1H), 7.49(d,1H), 7.05(d, 1H), 3.34(m, 2H), 1.73(m, 2H), 1.04(t, 3H). MS 538.0 m/z(M−H)⁻.

Example 722-[3-(5-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-fluorophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4-fluorophenol (292mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-fluorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-fluorophenyl)-2-fluoro-5-nitrobenzamide (676 mg, 2.3mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (318 mg, 50%). ¹H NMR (DMSO) δ 8.94(m,1H), 8.54(m, 1H), 7.95(m, 1H), 7.81(m, 2H), 7.41(m, 1H).

c) 2-(3-Nitro-6-propylaminophenyl)-5-fluorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-fluorobenzoxazole (221 mg, 0.8 mmol) andpropylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-5-fluorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-fluorobenzoxazole (126 mg, 0.4 mmol)the subtitle compound was obtained. The product was used directly in thenext step.

e)2-[3-(5-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-fluorobenzoxazole (114 mg, 0.4 mmol)and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the titlecompound was obtained (107 mg, 58%). ¹H NMR (DMSO) δ 8.40(m, 2H),8.30(s, 1H), 8.08(m, 2H), 7.79(m, 1H), 7.70(dd, 1H), 7.48(dd, 1H),7.28(m, 1H), 7.05(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS457.6 m/z (M−H)⁻.

Example 732-[3-(6,7-Difluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-3,4-difluorophenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-5,6-difluorophenol(334 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3mmol) the subtitle compound was obtained. The product was used directlyin the next step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-6,7-difluorobenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-3,4-difluorophenyl)-2-fluoro-5-nitrobenzamide (718 mg, 2.3mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (303 mg, 45%). ¹H NMR (DMSO) δ 8.92(m,1H), 8.57(m, 1H), 7.85(d, 1H), 7.81(m, 1H), 7.61(m, 1H).

c) 2-(3-Nitro-6-propylaminophenyl)-6,7-difluorobenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-6,7-difluorobenzoxazole (235 mg, 0.8 mmol)and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained.The product was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-6,7-difluorobenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-6,7-difluorobenzoxazole (133 mg, 0.4mmol) the subtitle compound was obtained. The product was used directlyin the next step.

e)2-[3-(6,7-Difluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-6,7-difluorobenzoxazole (121 mg, 0.4mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) thetitle compound was obtained (105 mg, 55%). ¹H NMR (DMSO) δ 8.41(dd, 1H),8.29(s, 1H), 8.25(t, 1H), 8.14(d, 1H), 8.06(d, 1H), 7.67(m, 1H), 7.50(m,2H), 7.04(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 475.7 m/z(M−H)⁻.

Example 742-[3-(5-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-5-methylphenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-4-methylphenol (283mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-5-methylbenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-5-methylphenyl)-2-fluoro-5-nitrobenzamide (667 mg, 2.3mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (345 mg, 55%). ¹H NMR (DMSO) δ 8.92(m,1H), 8.50(m, 1H), 7.79(t, 1H), 7.67(d, 1H), 7.39(t, 1H), 7.28(d, 1H),2.60(s, 3H).

c) 2-(3-Nitro-6-propylaminophenyl)-5-methylbenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-5-methylbenzoxazole (218 mg, 0.8 mmol) andpropylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-5-methylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-5-methylbenzoxazole (124 mg, 0.4 mmol)the subtitle compound was obtained. The product was used directly in thenext step.

e)2-[3-(5-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-methylbenzoxazole (112 mg, 0.4 mmol)and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the titlecompound was obtained (92 mg, 50%). ¹H NMR (DMSO) δ 8.60(t, 1H), 8.41(d,1H), 8.29(s, 1H), 8.08(m, 2H), 7.54(d, 1H), 7.45(d, 1H), 7.30(t, 1H),7.22(d, 1H), 6.99(d, 1H), 3.34(m, 2H), 2.59(s, 3H), 1.79(m, 2H), 1.12(t,3H). MS 454.1 m/z (M−H)⁻.

Example 752-[3-(4-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(2-Hydroxy-6-methylphenyl)-2-fluoro-5-nitrobenzamide

Prepared by the method of Example 15a), from 2-amino-3-methylphenol (283mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

b) 2-(3-Nitro-6-fluorophenyl)-4-methylbenzoxazole

Prepared by the method of Example 15b), fromN-(2-hydroxy-6-methylphenyl)-2-fluoro-5-nitrobenzamide (667 mg, 2.3mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) thesubtitle compound was obtained (327 mg, 52%). ¹H NMR (DMSO) δ8.92(m,1H), 8.50(m, 1H), 7.82-7.74(m; 2H), 7.70(s, 1H), 7.33(dd, 1H).

c) 2-(3-Nitro-6-propylaminophenyl)-4-methylbenzoxazole

Prepared by the method of Example 54a), from2-(3-nitro-6-fluorophenyl)-4-methylbenzoxazole (218 mg, 0.8 mmol) andpropylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. Theproduct was used directly in the next step without purification.

d) 2-(3-Amino-6-propylaminophenyl)-4-methylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-propylaminophenyl)-4-methylbenzoxazole (124 mg, 0.4 mmol)the subtitle compound was obtained. The product was used directly in thenext step.

e)2-[3-(4-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-4-methylbenzoxazole (112 mg, 0.4 mmol)and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the titlecompound was obtained (110 mg, 60%). ¹H NMR (DMSO) δ 8.46(t, 1H),8.41(dd, 1H), 8.03(s, 1H), 8.06(m, 2H), 7.61(m, 2H), 7.44(dd, 1H),7.22(d, 1H), 7.00(d, 1H), 3.34(m, 2H), 2.44(s, 3H), 1.74(m, 2H), 1.06(t,3H). MS 453.9 m/z (M−H)⁻.

Example 762-(3-[6-(2-Tetrahydrofuranylmethylaminocarbonyl)benzoxazol-2-yl]phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 4-(3-Nitrobenzamido)-3-hydroxybenzoic acid methyl ester

Prepared by the method of Example 15b), from methyl3-hydroxy-4-aminobenzoate (12.94 g, 77.0 mmol) and 3-nitrobenzoylchloride (14.29 g, 77.0 mmol) the subtitle compound was obtained (22.45g, 92%). The product was used directly in the next step withoutpurification.

b) 2-(3-Nitrophenyl)benzoxazole-6-carboxylic acid methyl ester

Prepared from the method of Example 15c), from4-(3-nitrobenzamido)-3-hydroxybenzoic acid methyl ester (20 g, 63.0mmol) and p-toluenesulfonic acid monohydrate (26.3 g, 138 mmol) thesubtitle compound was obtained (3.05 g, 16%). ¹H NMR (CDCl₃) δ 9.13(t,1H), 8.62(d, 1H), 8.44(dd, 1H), 8.33(s, 1H), 8.15(dd, 1H), 7.85(d, 1H),7.77(t, 1H), 4.00(s, 3H).

c) 2-(3-Nitrophenyl)benzoxazole-6-carboxylic acid

A solution of lithium hydroxide (1.78 g, 65.0 mmol) in water (10 ml) wasadded to a solution of 2-(3-nitrophenyl)benzoxazole-6-carboxylic acidmethyl ester (4.0 g, 14.8 mmol) in THF (30 ml). The reaction was heatedto 60° C. for 4 h. The cooled reaction mixture was acidified with 2M HCland the precipitate filtered, washed with water and dried under vacuumto give the subtitle compound (3.47 g, 92%). The product was useddirectly in the next step without purification.

d) 2-(3-Aminophenyl)benzoxazole-6-carboxylic acid

Prepared from the method of Example 15e), from2-(3-nitrophenyl)benzoxazole-6-carboxylic acid (3.28 g, 13.0 mmol) thesubtitle compound was obtained (2.67 g, 85%). ¹H NMR (DMSO) δ 8.25(s,1H), 8.00(dd, 1H), 7.85(d, 1H), 7.46(s, 1H), 7.38(d, 1H), 7.25(t, 1H),6.82(dt, 1H).

e)2-[3(5-Benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole6-carboxylic acid (2.50 g, 9.8 mmol) and1,2,4-benzenetricarboxylic acid benzyl ester (2.82 g, 10 mmol) thesubtitle compound was obtained (2.94 g, 60%). ¹H NMR (DMSO) δ 8.48(dd,1H), 8.38(m, 2H), 8.30(m, 2H), 8.15(d, 1H), 8.04 (dd, 1H), 7.93(d, 1H),7.86-7.77(m, 2H), 7.54(m, 2H), 7.48-7.38(m, 3H), 5.45(s, 2H).

f)2-[3-(6-Chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester

Prepared by the method of Example 15a), from2-[3-(5-benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid (2.50 g, 5.0 mmol) and oxalyl chloride (2.19 ml, 25 mmol) thesubtitle compound was obtained. The product was used directly in thenext step without purification.

g)2-(3-[6-(2-Tetrahydrofuranylmethylaminocarbonyl)benzoxazol-2-yl]phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

A solution of2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) in THF (1 ml) was added to asolution of tetrahydrofurfurylamine (14 mg, 0.14 mmol) in THF (1 ml)containing polymer bound morpholine (2.5 mmol g⁻¹, 72 mg). After shakingovernight, polymer bound isocyanate (2.0 mmol g⁻¹, 90 mg) was added andthe reaction shaken for 4 h. The reaction was filtered and the solventremoved under reduced pressure. The residue was suspended in dioxane andpalladium on carbon was added (spatula tip). The reaction vessel waspurged with hydrogen and stirred at room temperature overnight. Thereaction was filtered through celite and the filtrate concentrated togive the title compound (27 mg, 59%). ¹H NMR (DMSO) δ 8.74(t, 1H),8.44(dd, 1H), 8.37(m, 2H), 8.31-8.27(m, 3H), 8.12(d, 1H), 7.97(dd, 1H),7.90(d, 1H), 7.85-7.76(m, 1H), 4.00(m, 2H), 3.79(m, 1H), 3.65(m, 2H),1.98-1.77(4H, m). MS 510.2 m/z (M−H)⁻.

Example 772-[3-[6-(4-Piperonylpiperazine-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and 1-piperonylpiperazine (31 mg,0.14 mmol) the title compound was obtained (32 mg, 54%). ¹H NMR (DMSO) δ8.33(dd, 1H), 8.25(m, 2H), 8.17(dt, 1H), 8.01(d, 1H), 7.79-7.65(m, 4H),7.37(d, 1H), 6.77-6.72(m, 2H), 6.64(dd, 1H), 5.88(s, 2H) 3.45(s, 2H),3.40-3.2(bm, 4H) 2.48-2.22(bm, 4H). MS 629.2 m/z (M−H)⁻.

Example 782-[3-[6-(4-Piperazinoacetophenone-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and 4-piperazino acetophenone (31mg, 0.14 mmol) the title compound was obtained (25 mg, 42%). ¹H NMR(DMSO) δ 8.73(dd, 1H), 8.64(d, 2H), 8.57(d, 1H), 8.39(d, 1H),8.24-8.17(m, 2H), 8.12-8.04(m, 3H), 7.97(m, 1H), 7.46(d, 1H), 7.27(d,1H), 7.18(d, 1H), 3.70-3.45(bm, 8H), 2.73(s, 3H). MS 613.5 m/z (M−H)⁻.

Example 792-[3-[6-(3-Trifluoromethylphenyl)piperazine-1-carbonyl]benzoxazol-2-yl]phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and1-(3-trifluoromethylphenyl)piperazine (32 mg, 0.14 mmol) the titlecompound was obtained (33 mg, 57%). ¹H NMR (DMSO) δ 8.44(dd, 1H),8.36(m, 2H), 8.30(dt, 1H), 8.12(d, 1H), 7.96-7.91(m, 2H), 7.86-7.77(m,2H), 7.52(dd, 1H), 7.45(t, 1H), 7.27-7.21(m, 2H), 7.10(d, 1H),3.90-3.40(bm, 8H). MS 571.0 m/z (M−H)⁻.

Example 802-[3-[6-(3-Carbamoylpiperidine-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and nipecotamide (18 mg, 0.14 mmol)the title compound was obtained (18 mg, 37%). ¹H NMR (DMSO) δ 8.44(dd,1H), 8.36(m, 2H), 8.29(dt, 1H), 7.95-7.76(m, 4H), 7.44(dd, 1H), 4.02(m,1H), 3.18(bm, 2H), 2.87(bm, 2H), 1.70-1.38(m, 4H). MS 536.8 m/z (M−H)⁻.

Example 812-[3-[6-(4-Methoxybenzylaminocarbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and 4-methoxybenzylamine (19 mg,0.14 mmol) the title compound was obtained (22 mg, 45%). ¹H NMR (DMSO) δ9.20(t, 1H), 8.43(dd, 1H), 8.36(m, 2H), 8.30(m, 2H), 8.09(d, 1H),7.99(dd, 1H), 7.91(d, 1H), 7.82-7.89(m, 2H), 7.28(d, 2H), 6.89(d, 2H),4.45(d, 2H), 3.73(s, 3H). MS 545.9 m/z (M−H)⁻.

Example 822-[3-[6-(3,4-Dimethoxybenzylamino)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 76 g), from2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol) and 3,4-dimethoxybenzylamine (23mg, 0.14 mmol) the title compound was obtained (17 mg, 33%). ¹H NMR(DMSO) δ 9.14(t, 1H), 8.44(dd, 1H), 8.36(m, 2H), 8.29(m, 2H), 8.11(d,1H), 7.99(dd, 1H), 7.91(d, 1H), 7.85-7.76(m, 2H), 6.97(d, 1H),6.92-6.85(m, 2H), 4.45(d, 2H), 3.73(s, 3H), 3.71(s, 3H). MS 576.2 m/z(M−H)⁻.

Example 832-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole-6-carboxylic acid (70 mg, 0.27 mmol) and1,2,4-benzenetricarboxylic anhydride (53 mg, 0.27 mmol) the titlecompound was obtained (34 mg, 29%). ¹H NMR (DMSO) δ 8.38(m, 1H), 8.31(m,2H), 8.06(dd, 1H), 7.92(m, 2H), 7.86(s, 1H), 7.78(m, 3H). MS 429 m/z(M+H)⁺.

Example 842-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid methyl ester a) 2-(3-Aminophenyl)benzoxazole-6-carboxylic acidmethyl ester

Prepared by the method of Example 15e), from2-(3-nitrophenyl)benzoxazole-6-carboxylic acid methyl ester (3.00 g,10.05 mmol) the subtitle compound was obtained, (1.58 mg, 59%). Theproduct was used directly in the next step without purification.

b)2-[3-(5-Carboxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid methyl ester

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole-6-carboxylic acid methyl ester (100 mg,0.37 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.37 mmol)the title compound was obtained (148 mg, 90%). ¹H NMR (DMSO) δ 8.45(dd,1H), 8.39(m, 1H), 8.32(m, 3H), 8.13(d, 1H), 8.05(dd, 1H), 7.96(d, 1H),7.80(m, 2H), 3.91(s, 3H). MS 443 m/z (M+H)⁺.

Example 852-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-7-carboxylicacid a) Methyl 2-hydroxy-3-nitrobenzoate

A solution of 3-hydroxy-2-nitrobenzoic acid (10.00 g, 5.46 mmol) inmethanolic hydrochloric acid (50 ml) was heated to reflux overnightunder an argon atmosphere. The cooled reaction mixture was concentratedto a green solid, which was then partitioned between saturated sodiumhydrogen carbonate solution (50 ml) and ethyl acetate (50 ml). Theaqueous layer was extracted with ethyl acetate (2×50 ml) and thecombined organic layers dried over sodium sulfate and the solventremoved under reduced pressure to give the subtitle compound (885 mg,81%). ¹H NMR (DMSO) δ 7.58(t, 1H), 7.47(dd, 1H), 7.40(dd, 1H), 3.89(s,3H).

b) Methyl 2-hydroxy-3-aminobenzoate

Prepared by the method of Example 15e), from methyl3-hydroxy-2-nitrobenzoate (875 mg, 4.44 mmol) the subtitle compound wasobtained (776 mg, 99%). MS 168.2 m/z (M+H)⁺.

c) 3-(3-Nitrobenzamido)-2-hydroxybenzoic acid methyl ester

Prepared by the method of Example 15b), from methyl3-hydroxy-2-aminobenzoate (776 mg, 4.64 mmol), 3-nitrobenzoylchloride(861.4 mg, 4.64 mmol) and triethylamine (939 mg, 9.28 mmol) the subtitlecompound was obtained (1.27 g, 87%). MS 317.1 m/z (M+H)⁺.

d) 2-(3-Nitrophenyl)benzoxazole-7-carboxylic acid methyl ester

Prepared by the method of Example 15c), from3-(3-nitrobenzamido)-2-hydroxybenzoic acid methyl ester (1.00 mg, 3.16mmol) and p-toluenesulfonic acid monohydrate (1.26 mg, 6.64 mmol) thesubtitle compound was obtained (600 mg, 64%). ¹H NMR (DMSO) δ 8.95(m,1H), 8.7(m, 1H), 8.59(dd, 1H), 8.23(d, 1H), 8.05(m, 2H), 7.70(t, 1H).

e) 2-(3-Nitrophenyl)benzoxazole-7-carboxylic acid

Prepared by the method of Example 76c), from2-(3-nitrophenyl)benzoxazole-7-carboxylic acid methyl ester (600 mg,2.01 mmol) and lithium hydroxide (240 mg, 10.06 mmol) the subtitlecompound was obtained, (442 mg, 77%). The product was used directly innext step without purification.

f) 2-(3-Aminophenyl)benzoxazole-7-carboxylic acid

Prepared by the method of Example 15e), from2-(3-nitrophenyl)benzoxazole-7-carboxylic acid (400 mg, 1.40 mmol) thesubtitle compound was obtained (227 mg, 63%). The product was useddirectly in the next step without purification.

g)2-[3-(5-Carboxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-7-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole-7-carboxylic acid (100 mg, 0.39 mmol) and1,2,4-benzenetricarboxylic anhydride (75 mg, 0.39 mmol) the titlecompound was obtained, (148 mg, 32%). ¹H NMR (DMSO) δ 8.50(m, 2H),8.39(m, 2H), 8.17(m, 2H), 8.01(m, 1H), 7.88(m, 2H), 7.63(t, 1H). MS 429m/z (M+H)⁺.

Example 862-[3-(5-Benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid a) 1,2,4-Benzenetricarboxylic anhydride benzyl ester

A solution of benzyl alcohol (513 mg, 4.75 mmol) and pyridine (375 mg,4.75 mmol) in toluene (25 ml) were added dropwise with stirring to asolution of trimellitic anhydride acid chloride (1.00 g, 4.75 mmol) intoluene (25 ml). After addition was complete the reaction was stirred atroom temperature for 3 h. The reaction mixture was concentrated to givethe subtitle compound as a white solid (1.08 mg, 81%). ¹H NMR (CDCl₃) δ8.60(s, 1H), 8.51(d, 1H), 8.02(d, 1H), 7.37(m, 5H).

b)2-[3-(5-Benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole-6-carboxylic (459 mg, 1.80 mmol) and1,2,4-benzenetricarboxylic anhydride benzyl ester (509 mg, 1.80 mmol)the title compound was obtained, (312 mg 50%). ¹H NMR (DMSO) δ 8.40(dd,1H), 8.29(m, 2H), 8.22(m, 2H), 8.06(d, 1H), 7.95(m, 1H), 7.84(m, 1H),7.72(m, 2H), 7.45(m, 2H), 7.34(m, 3H), 5.35(s, 2H). MS 517 m/z (M−H)⁻.

Example 872-[3-(5-Methyloxycarbonyl-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid a) 1,2,4-Benzenetricarboxylic anhydride methyl ester

Prepared by the method of Example 86a), from trimellitic anhydride acidchloride (200 mg, 0.95 mmol), pyridine (75 mg, 0.95 mmol) and methanol(38 mg, 0.95 mmol) the subtitle compound was obtained as a white solid(143 mg, 73%). The product was used directly in the next step withoutpurification.

b)2-[3-(5-Methyloxycarbonyl-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid

Prepared by the method of Example 1b), from2-(3-aminophenyl)benzoxazole-6-carboxylic (167 mg, 0.66 mmol) and1,2,4-benzenetricarboxylic anhydride methyl ester (136 mg, 0.66 mmol)the title compound was obtained (157 mg, 54%). ¹H NMR (DMSO) δ 8.48(dd,1H), 8.34(m, 4H), 8.15(d, 1H), 8.04(dd, 1H), 7.86(m, 3H), 3.95(s, 3H).MS 443 m/z (M++H)⁺.

Example 882-[5-(5-Bromobenzoxazol-2-yl)-2-methoxyphenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Amino-4-methoxyphenyl)-5-bromobenzoxazole

Prepared by the method of Example 1a), from 3-amino-4-methoxybenzoicacid (1.84 g, 11.0 mmol) and 2-amino-4-bromophenol (2.0 g, 11.0 mmol)the subtitle compound was obtained (2.0 g, 55%). ¹H NMR (CDCl₃) δ7.85(t, 1H), 7.64(dd, 1H), 7.58(d, 1H), 7.41(d, 1H), 6.90(d, 1H),3.95(s, 3H).

b)2-[5-(5-Bromobenzoxazol-2-yl)-2-methoxyphenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-bromobenzoxazole (166 mg, 0.5 mmol) and1,2,4-benzenetricarboxylic anhydride (100 mg, 0.5 mmol) the titlecompound was obtained (238 mg, 93%). ¹H NMR (DMSO) δ 8.44(dd, 1H),8.32(m, 3H), 8.10(d, 1H), 8.02(d, 1H), 7.77(d, 1H), 7.57(dd, 1H),7.48(d, 1H). MS 490.9 m/z (M−H)⁻.

Example 892-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thienyl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-(3-thienyl)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-chlorophenyl)-5-phenylbenzoxazole (177 mg, 0.51 mmol) andthiophene-3-boronic acid (97 mg, 0.76 mmol) the subtitle compound wasobtained (150 mg, 74%). ¹H NMR (DMSO) δ 8.67(d, 1H), 8.48(dd, 1H),8.12(d, 1H), 7.91(m, 2H), 7.83(m, 1H), 7.79-7.77(m, 4H), 7.51(m, 2H),7.40(t, 1H), 7.22(dd, 1H).

b) 2-(3-Amino-4-(3-thienyl)phenyl)-5-phenylbenzoxazole

Prepared by the method of Example 39b), from2-(3-nitro-4-(3-thienyl)phenyl)-5-phenylbenzoxazole (88 mg, 0.22 mmol)the subtitle compound was obtained. The product was used directly in thenext step without purification.

c)2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thienyl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-(3-thienyl)phenyl)-5-phenylbenzoxazole (61 mg, 0.16 mmol)and 1,2,4-benzenetricarboxylic anhydride (32 mg, 0.16 mmol) the titlecompound was obtained (66 mg, 75%). ¹H NMR (DMSO) δ 8.50(d, 1H), 8.41(m,2H), 8.30(s, 1H), 8.07(m, 2H), 7.90(m, 2H), 7.75(m, 3H), 7.62(m, 1H),7.55(m, 1H), 7.50(m, 2H), 7.40(t, 1H), 7.11 (dd, 1H). MS 540.7 m/z(M−H)⁻.

Example 902-[2-Fluoro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(5-Phenyl-2-hydroxy-5-phenyl)-3-nitro-4-fluorobenzamide

Prepared by the method of Example 15b), from 2-amino-4-phenylphenol(8.80 g, 48.0 mmol) and 3-nitro-4-fluorobenzoyl chloride (11.19 g, 55mmol) the subtitle compound was obtained (15.46 g, 92%). The product wasused directly in the next step without purification.

b) 2-(3-Nitro-4-fluoro)-5-phenylbenzoxazole

Prepared by the method of Example 15c), fromN-(5-phenyl-2-hydroxyphenyl)-3-nitro-4-fluorobenzamide (15.46 g, 44.0mmol) and p-toluenesulfonic acid monohydrate (16.74 g, 88 mmol) thesubtitle compound was obtained (3.25 g, 23%). ¹H NMR (DMSO) δ 8.82(dd,1H), 8.59(m, 1H), 8.11(d, 1H), 7.93-7.73(m, 5H), 7.50(m, 2H), 7.40(t,1H).

c) 2-(3-Amino-4-fluoro)-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-fluoro)-5-phenylbenzoxazole (100 mg, 0.30 mmol) thesubtitle compound was obtained (81 mg, 89%). ¹H NMR (DMSO) δ 7.95(d,1H), 7.72(dd, 1H), 7.65-7.58(m, 5H), 7.48(m, 2H), 7.38(t, 1H), 7.14(m,1H).

d)2-[2-Fluoro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-fluoro)-5-phenylbenzoxazole (78 mg, 0.26 mmol) and1,2,4-benzenetricarboxylic anhydride (49 mg, 0.26 mmol) the titlecompound was obtained (80 mg, 65%). ¹H NMR (DMSO) δ 8.54-8.38(m, 4H),8.16(d, 1H), 8.08(d, 1H), 7.88(d, 1H), 7.80-7.73(m, 4H), 7.50(m, 2H),7.39(t, 1H). MS 477.3 m/z (M−H)⁻.

Example 912-[2-Chloro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) N-(5-Phenyl-2-hydroxyphenyl)-3-nitro-4-chlorobenzamide

Prepared by the method of Example 15b), from 3-nitro-4-chlorobenzoylchloride (5.28 g, 24.0 mmol) and 4-phenyl-2-aminophenol (3.92 g, 21.0mmol) the subtitle compound was obtained. The product was used directlyin the next step without purification.

b) 2-(3-Nitro-4-chlorophenyl)-5-phenylbenzoxazole

Prepared by the method of Example 15c), fromN-(5-phenyl-2-hydroxyphenyl)-3-nitro-4-chlorobenzamide (3.76 g, 10 mmol)and p-toluenesulfonic acid monohydrate (3.80 g, 20 mmol) the subtitlecompound was obtained (1.28 g, 40%). MS 351.1 (M+H)⁺.

c) 2-(3-Amino-4-chlorophenyl-5-phenylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-chlorophenyl)-5-phenylbenzoxazole (240 mg, 0.68 mmol) thesubtitle compound was obtained (35 mg, 16%). ¹H NMR (CDCl₃) δ 7.95(s,1H), 7.70-7.59(m, 6H), 7.48(m, 2H), 7.40(m, 2H).

d)2-[2-Chloro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15e), from2-(3-amino-4-chlorophenyl)-5-phenylbenzoxazole (43 mg, 0.13 mmol) and1,2,4-benzenetricarboxylic acid (26 mg, 0.13 mmol) the title compoundwas obtained (10 mg, 15%). ¹H NMR (DMSO) δ 8.58(d, 1H), 8.48(dd, 1H),8.38(m, 2H), 8.17(d, 1H), 8.08(d, 1H), 7.99(d, 1H), 7.88(d, 1H), 7.76(m,3H), 7.50(m, 2H), 7.39(t, 1H). MS 492.8 m/z (M−H)⁻.

Example 922-[2-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) andbenzothiophene-2-boronic acid (153 mg, 0.85 mmol) the subtitle compoundwas obtained (200 mg, 15%). MS 403.1 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(2-benzothiophenyl) benzoxazole (200 mg,0.50 mmol) and palladium on carbon (10%) (10 mg) in dioxane (10 ml), thesubtitle compound was obtained.(40 mg, 86%). MS 373.2 m/z (M+H)⁺.

c)2-[2-Methoxy-5-[5-(2-benzothiopheneyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-4-methoxyphenyl-5-(2-benzothiophenyl)benzoxazole (120 mg,0.32 mmol) and 1,2,4-benzenetricarboxylic anhydride (62 mg, 0.32 mmol)the title compound was obtained. (41 mg, 23%). ¹H NMR (DMSO) δ 13.82(s,1H), 8.46(dd, 1H), 8.38(d, 1H), 8.35(m, 2H), 8.18(d, 1H), 8.13(d, 1H),8.00(d, 1H), 7.96(s, 1H), 7.85(m, 3H), 7.50(d, 1H), 7.40(m, 2H), 3.90(s,3H). MS 547.2 m/z (M+H)⁺.

Example 932-[2-Methoxy-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2(3-Nitro-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-chloro-3-methylphenylboronic acid (145 mg, 0.85 mmol) the subtitlecompound was obtained (85 mg, 25%). MS 395 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole (85mg, 0.21 mmol) the subtitle compound was obtained (79 mg, 100%). MS 365m/z (M+H)⁺.

c)2-[2-Methoxy-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole (79mg, 0.22 mmol) and 1,2,4-benzenetricarboxylic anhydride (42 mg, 0.22mmol) the title compound was obtained (22 mg, 19%). ¹H NMR (DMSO) δ8.55(dd, 1H), 8.44(m, 3H), 8.22(d, 1H), 8.14(m, 1H), 7.90(m, 3H),7.65(m, 3H), 4.00(s, 3H), 2.45(s, 3H). MS 527 m/z (M+H)⁺.

Example 942-[2-Methoxy-5-[5-(4-fluoro-3-formylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-4-methoxyphenyl)-5-(4-fluoro-3-formylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and4-fluoro-3-formylphenylboronic acid (143 mg, 0.85 mmol) the subtitlecompound was obtained (146 mg, 44%). MS 393 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-fluoro-3-formylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-fluoro-3-formylbenzene)benzoxazole (146mg, 0.37 mmol) the subtitle compound was obtained (62 mg, 46%). MS 363m/z (M+H)⁺.

c)2-[2-Methoxy-5-[5-(4-fluoro-3-formylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(4-fluoro-3-formylbenzene)benzoxazole (62mg, 0.17 mmol) and 1,2,4-benzenetricarboxylic anhydride (62 mg, 0.17mmol) the title compound was obtained (48 mg, 53%). ¹H NMR (DMSO) δ10.40(s, 1H), 8.53(dd, 1H), 8.45(m, 3H), 8.22(m, 4H), 7.95(d, 1H),7.82(dd, 1H), 7.60(m, 2H), 3.95(s, 3H). MS 537 m/z (M+H)⁺.

Example 952-[2-Methoxy-5-[5-(3,4-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and3,4-difluorophenylboronic acid (134 mg, 0.85 mmol) the subtitle compoundwas obtained (68 mg, 21%). MS 383 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole (68 mg,0.18 mmol) the subtitle compound was obtained (63 mg, 100%). MS 353 m/z(M+H)⁺.

c)2-[2-Methoxy-5-[5-(3,4-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole (63 mg,0.18 mmol) and 1,2,4-benzenetricarboxylic anhydride (35 mg, 0.18 mmol)the title compound was obtained (25 mg, 27%). ¹H NMR (DMSO) δ 8.53(dd,1H), 8.42(m, 3H), 8.18(m, 2H), 7.94(m, 2H), 7.79(dd, 1H), 7.60(m, 3H),3.95(s, 3H). MS 527 m/z (M+H)⁺.

Example 962-[2-Methoxy-5-[5-(4-ethylsulfonylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(4-ethylsulfonylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and4-(ethylsulfonyl)phenylboronic acid (214 mg, 1.75 mmol) the subtitlecompound was obtained (88 mg, 12%). MS 439 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-ethylsulfonylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-ethylsulfonyphenyl) benzoxazole (88 mg,0.20 mmol) the subtitle compound was obtained (63 mg, 78%). MS 409 m/z(M+H)⁺.

c)2-[2-Methoxy-5-[5-(4-ethylsulfonylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(4-ethylsulfonyl phenyl)benzoxazole (63mg, 0.15 mmol) and 1,2,4-benzenetricarboxylic anhydride (29 mg, 0.15mmol) the title compound was obtained (34 mg, 39%). ¹H NMR (DMSO) δ8.57(dd, 1H), 8.57(m,4H), 8.30(d, 1H) 8.10(m, 4H), 8.03(d, 1H), 7.92(dd,1H), 7.61(d, 1H), 4.00(s, 3H), 3.45(q, 2H), 1.25(t, 3H). MS 583 m/z(M+H)⁺.

Example 972-[2-Methoxy-5-[5-(4-N,N-dimethylaminophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3Nitro-4-methoxyphenyl)-5-(4-N,N-dimethylaminophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and4-(N,N-dimethylamino)phenylboronic acid (285 mg, 1.75 mmol) the subtitlecompound was obtained (114 mg, 17%). MS 390 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(4-N,N-dimethylaminophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(4-N,N-dimethylamino phenyl)benzoxazole(144 mg, 0.30 mmol) the subtitle compound was obtained (79 mg, 76%). MS360 m/z (M+H)⁺.

c)2-[2-Methoxy-5-[5-(4-N,N-dimethylaminophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(4-N,N-dimethylaminophenyl)benzoxazole (79mg, 0.22 mmol) and 1,2,4-benzenetricarboxylic anhydride (42 mg, 0.22mmol) the title compound was obtained (52 mg, 44%). ¹H NMR (DMSO) δ8.46(d, 1H), 8.40(m, 3H), 8.20(d, 1H), 7.98(s, 1H), 7.82(d, 1H), 7.65(m,3H), 7.55(d, 1H), 6.89(d, 2H), 3.95(s, 3H), 3.00(s, 6H). MS 534 m/z(M+H)⁺.

Example 982-[2-Methoxy-5-[5-(2,3-dichlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and2,3-dichlorophenylboronic acid (329 mg, 1.72 mmol) the subtitle compoundwas obtained (288 mg, 60%). MS 415 m/z (M+H)⁺.

b) 2-(3-Amino-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole (288 mg,0.70 mmol) the subtitle compound was obtained (238 mg, 82%). The productwas used directly in the next step without purification.

c)2-[2Methoxy-5-[5-(2,3-dichlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(3-amino-4-methoxyphenyl)-5-(2,3-dichlorophenyl)benzoxazole (238 mg,0.60 mmol) and 1,2,4-benzenetricarboxylic anhydride (19 mg, 0.60 mmol)the title compound was obtained (191 mg, 57%). ¹H NMR (DMSO) δ 8.46(dd,1H), 8.35(m, 3H), 8.13(d, 1H), 7.84(m, 2H), 7.70(m, 1H), 7.47(m, 4H),3.87(s, 3H). MS 560 m/z (M+H)⁺.

Example 992-[4-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-Methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) andbenzothiophene-2-boronic acid (306 mg, 1.71 mmol) the subtitle compoundwas obtained (569 mg, 123%). The product was used directly in the nextstep without purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole (485 mg,1.37 mmol) the subtitle compound was obtained (420 mg, 82%). MS 373.2m/z (M+H)⁺.

c)2-[4-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole (140 mg,0.38 mmol) and 1,2,4-benzenetricarboxylic anhydride (72 mg, 0.38 mmol)the title compound was obtained (100 mg, 22%). ¹H NMR (DMSO) δ 13.79(s,1H), 8.44(dd, 1H), 8.34(s, 1H), 8.22(m, 2H), 8.11(d, 1H), 8.01(d, 1H),7.97(s, 1H), 7.92(d, 1H), 7.87(m, 2H), 7.73(dd, 1H), 7.48(d, 1H),7.40(m, 2H), 4.04(s, 3H). MS 547.0 m/z (M+H)⁺.

Example 1002-[4-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and4-chlorophenylboronic acid (269 mg, 1.71 mmol) the subtitle compound wasobtained (323 mg, 74%). The product was used directly in the next stepwithout purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(4-chlorophenyl) benzoxazole (310 mg, 0.93mmol) the subtitle compound was obtained (225 mg, 69%). MS 351.2 m/z(M+H)⁺.

c)2-[4-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(4-chlorophenyl) benzoxazole (75 mg, 0.21mmol) and 1,2,4-benzenetricarboxylic anhydride (41 mg, 0.21 mmol) thetitle compound was obtained (105 mg, 45%). ¹H NMR (DMSO) δ 13.72(s, 1H),8.42(dd, 1H), 8.32(s, 1H), 8.20(d, 1H), 8.09(m, 2H), 7.87(d, 1H),7.78(d, 2H), 7.72(m, 2H), 7.54(d, 2H), 7.48(d, 1H), 4.04(s, 3H). MS525.3 m/z (M+H)⁺.

Example 1012-[4-Methoxy-5-[5-(3-chloro-4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and3-chloro-4-fluorophenylboronic acid (299 mg, 1.71 mmol) the subtitlecompound was obtained (277 mg, 47%). The product was used directly inthe next step without purification

b) 2-(3-Amino-6-methoxyphenyl)-5-(3-chloro,4-fluoro)phenylbenzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole (277mg, 0.81 mmol) the subtitle compound was obtained (180 mg, 60%). MS369.2 m/z (M+H)⁺.

c)2-[4-Methoxy-5-[5-(3-chloro-4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(3-chloro-4-fluoro phenyl)benzoxazole (60mg, 0.16 mmol) and 1,2,4-benzenetricarboxylic anhydride (31 mg, 0.16mmol) the title compound was obtained (75 mg, 86%). ¹H NMR (DMSO) δ13.80(s, 1H), 8.43(d, 1H), 8.32(s, 1H), 8.21(d, 1H), 8.15(s, 1H),8.10(d, 1H), 7.99(dd, 1H), 7.88(d, 1H), 7.75(m, 3H), 7.53(t, 1H),7.47(d, 1H), 4.03(s, 3H). MS 542.6 m/z (M+H)⁺.

Example 1022-[4-Methoxy-5-[5-(4-trifluoromethylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3Nitro-6-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and4-trifluoromethylphenylboronic acid (326 mg, 1.71 mmol) the subtitlecompound was obtained (312 mg, 52%). The product was used directly inthe next step without purification

b) 2-(3-Amino-6-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole

Prepared by the method of 15e), from2-(3-nitro-6-methoxyphenyl)-5-(4-trifluoromethylphenyl) benzoxazole (312mg, 0.88 mmol) the subtitle compound was obtained (270 mg, 80%). MS385.2 m/z (M+H)⁺.

c)2-[4-Methoxy-5-[5-(4-trifluoromethylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(4-trifluoromethylphenyl)benzoxazole (90mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (45 mg, 0.23mmol) the title compound was obtained (102 mg, 79%). ¹H NMR (DMSO) δ13.74(s, 1H), 8.43(d, 1H), 8.33(s, 1H), 8.22(d, 1H), 8.20(d, 1H),8.10(d, 1H), 7.99(d, 2H), 7.93(d, 1H), 7.83(m, 3H), 7.72(dd, 1H),7.48(d, 1H), 4.03(s, 3H). MS 559.3 m/z (M+H)⁺.

Example 1032-[4-Methoxy-5-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-methoxyphenyl)-5-(2-benzofuranyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and2-benzofuranboronic acid (278 mg, 1.71 mmol) the subtitle compound wasobtained (342 mg, 61%). The product was used directly in the next stepwithout purification

b) 2-(3-Amino-6-methoxyphenyl)-5-(2-benzofuranyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(2-benzofuranyl) benzoxazole (342 mg, 1.05mmol) the subtitle compound was obtained (315 mg, 91%). MS 357.2 m/z(M+H)⁺.

c)2-[4-Methoxy-5-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(2-benzofuranyl) benzoxazole (105 mg, 0.29mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.29 mmol) thetitle compound was obtained (98 mg, 63%). ¹H NMR (DMSO) δ 13.74(s, 1H),8.43(dd, 1H), 8.32(d, 2H), 8.21(d, 1H), 8.10(d, 1H), 8.02(dd, 1H),7.92(d, 1H), 7.72(dd, 1H), 7.67(t, 2H), 7.54(s, 1H), 7.47(d, 1H),7.31(m, 2H), 4.03(s, 3H). MS 531.2 m/z (M+H)⁺.

Example 1042-[4-Methoxy-5-[5-(3,5-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6methoxyphenyl)-5-(3-difluorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and3,5-difluorophenylboronic acid (326 mg, 1.71 mmol) the subtitle compoundwas obtained (271 mg, 28%). The product was used directly in the nextstep without purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole (271 mg,0.84 mmol), the subtitle compound was obtained (210 mg, 67%). MS 353.2m/z (M+H)⁺.

c)2-[4-Methoxy-5-[5-(3,5-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(3,5-difluorophenyl) benzoxazole (70 mg,0.20 mmol) and 1,2,4-benzenetricarboxylic anhydride (38 mg, 0.20 mmol)the title compound was obtained (72 mg, 68%). ¹H NMR (DMSO) δ 13.79(s,1H), 8.42(dd, 1H), 8.33(s, 1H), 8.23(d, 1H), 8.21(d, 1H), 8.10(d, 1H),7.90(d, 1H), 7.83(dd, 1H), 7.72(dd, 1H), 7.56(m, 2H), 7.48(d, 1H),7.26(m, 1H), 4.03(s, 3H). MS 527.3 m/z (M+H)⁺.

Example 1052-[4-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and3,4-methylenedioxyphenylboronic acid (285 mg, 1.71 mmol) the subtitlecompound was obtained (270 mg, 48%). The product was used directly inthe next step without purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (270mg, 0.82 mmol) the subtitle compound was obtained (150 mg, 51%). MS361.2 m/z (M+H)⁺.

c)2-[4-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (50mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (27 mg, 0.14mmol) the title compound was obtained (72 mg, 92%). ¹H NMR (DMSO) δ13.85(s, 1H), 8.44(dd, 1H), 8.33(s, 1H), 8.21(d, 1H), 8.11(d, 1H),8.02(d, 1H), 7.83(d, 1H), 7.71(dd, 1H), 7.66(dd, 1H), 7.47(d, 1H),7.35(d, 1H), 7.22(dd, 1H), 7.03(d, 1H), 6.08(s, 2H), 4.03(s, 3H). MS535.1 m/z (M+H)⁺.

Example 1062-[4-Methoxy-5-[5-(3-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and3-methoxyphenylboronic acid (261 mg, 1.71 mmol) the subtitle compoundwas obtained (280 mg, 51%). The product was used directly in the nextstep without purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (280 mg, 0.89mmol) the subtitle compound was obtained (150 mg, 49%). MS 347.3 m/z(M+H)⁺.

c)2-[4-Methoxy-5-[5-(3-methoxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(3-methoxyphenyl)benzoxazole (50 mg, 0.14mmol) and 1,2,4-benzenetricarboxylic anhydride (28 mg, 0.14 mmol) thetitle compound was obtained (52 mg, 71%). ¹H NMR (DMSO) δ 8.43(d, 1H),8.33(s, 1H), 8.22(d, 1H), 8.10(m, 2H), 7.87(d, 1H), 7.74(m, 2H), 7.48(d,1H), 7.41(t, 1H), 7.30(m, 2H), 6.96(dd, 1H), 4.04(s, 3H), 3.85(s, 3H).MS 521.3 m/z (M+H)⁺.

Example 1072-[4-Methoxy-5-[5-(4-methylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-methoxyphenyl)-5-(4-methylphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and4-methylphenylboronic acid (234 mg, 1.71 mmol) the subtitle compound wasobtained (273 mg, 53%). The product was used directly in the next stepwithout purification.

b) 2-(3-Amino-6-methoxyphenyl)-5-(4-methylphenyl)benzoxazole

Prepared by the method of Example 15e), from2-(3-nitro-6-methoxyphenyl)-5-(4-methylphenyl) benzoxazole (273 mg, 0.92mmol) the subtitle compound was obtained (225 mg, 74%). MS 331.3 m/z(M+H)⁺.

c)2-[4-Methoxy-5-[5-(4-methylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-methoxyphenyl)-5-(4-methylphenyl) benzoxazole (75 mg, 0.23mmol) and 1,2,4-benzenetricarboxylic anhydride (44 mg, 0.23 mmol) thetitle compound was obtained (78 mg, 67%). ¹H NMR (DMSO) δ 8.43(dd, 1H),8.33(s, 1H), 8.21(d, 1H), 8.10(d, 1H), 8.04(d, 1H), 7.85(d, 1H), 7.71(m,2H),7.63(d, 2H), 7.46(d, 1H), 7.30(d, 2H), 4.03(s, 3H), 2.36(s, 3H). MS505.1 m/z (M+H)⁺.

Example 1082-[4-Propylamino-3-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(2-Fluoro-5-nitrophenyl)-5-(2-benzofuranyl)benzoxazole

Prepared by the method of Example 15d), from2-(2-fluoro-5-nitrophenyl)-5-bromobenzoxazole (1.00 g, 3.0 mmol) andbenzofuran-2-boronic acid (728 mg, 4.50 mmol) the subtitle compound wasobtained (208 mg, 18%). The product was used directly in the next stepwithout purification.

b) 2-(2-Propylamino-5nitrophenyl)-5-(2-benzofuranyl)benzoxazole

Prepared by the method of Example 54a), from2-(2-fluoro-5-nitrophenyl)-5-(2-benzofuranyl)benzoxazole (200 mg, 0.53mmol), and propylamine (3 ml) the subtitle compound was obtained (199mg, 91%). The product was used directly in the next step withoutpurification.

c) 2-(2-Propylamino-5-aminophenyl)-5-(2-benzofuranyl)benzoxazole

Prepared by the method of Example 47b), from2-(2-propylamino-5-nitrophenyl)-5-(2-benzofuranyl)benzoxazole (190 mg,0.46 mmol) and zinc (300 mg, 4.6 mmol) the subtitle compound wasobtained (150 mg, 85%). The product was used directly in the next stepwithout purification.

d)2-[4-Propylamino-3-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 1b), from2-(2-propylamino-5-aminophenyl)-5-(2-benzofuranyl)benzoxazole (50 mg,0.13 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.13 mmol)the title compound was obtained (40 mg, 55%). ¹H NMR (DMSO) δ 8.53(t,1H), 8.46(dd, 1H), 8.37(d, 2H), 8.18(d, 1H), 8.12(d, 1H), 8.05(dd, 1H),7.93(d, 1H), 7.72(m, 2), 7.60(s, 1H), 7.54(dd, 1H), 7.36(m, 2H), 7.10(d,1H), 3.44(m, 2H), 1.84(m, 2H), 1.15(t, 3H). MS 556 m/z (M−H)⁻.

Example 1092-[4-Propylamino-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol)and 3,4-methylenedioxyphenylboronic acid (264 mg, 1.59 mmol) thesubtitle compound was obtained (337 mg, 51%). The product was useddirectly in the next step without purification.

b) 2-(3-Amino-6-propylaminophenyl)-5-(methylenedioxy)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(3,4-methylenedioxyphenyl) benzoxazole(337 mg, 0.81 mmol) and zinc (530 mg, 8.1 mmol) the subtitle compoundwas obtained (313 mg, 100%). MS 388.3 m/z (M+H)⁺.

c)2-[4-Propylamino-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole(157 mg, 0.40 mmol) and 1,2,4-benzenetricarboxylic anhydride (76 mg,0.40 mmol) the title compound was obtained (82 mg, 36%). ¹H NMR (DMSO) δ13.78(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.30(s, 1H), 8.12(d, 1H),8.07(d, 1H), 8.00(d, 1H), 7.78(d, 1H), 7.64(dd, 1H), 7.47(dd, 1H),7.35(d, 1H), 7.24(dd, 1H), 7.04(d, 1H), 7.01(d, 1H), 6.08 (s, 2H),3.35(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 562.2 m/z (M+H)⁺.

Example 1102-[4-Propylamino-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-propylaminophenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol)and benzothiophene-2-boronic acid (283 mg, 1.59 mmol) the subtitlecompound was obtained (386 mg, 57%). The product was used directly inthe next step without purification.

b) 2-(3-Amino-6-propylaminophenyl)-5-(2-benzothiophenyl)benzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(2-benzothiophenyl)benzoxazole (386mg, 0.90 mmol) and zinc (589 mg, 9.0 mmol) the subtitle compound wasobtained (154 mg, 100%). MS 400.3 m/z (M+H)⁺.

c)2-[4-Propylamino-5-[5-(2-benzothiophenyl)phenylbenzoxazol-2-yl]phenyl]dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(2-benzothiophenyl)benzoxazole (180mg, 0.45 mmol) and 1,2,4-benzenetricarboxylic anhydride (86 mg, 0.45mmol) the title compound was obtained (100 mg, 39%). ¹H NMR (DMSO) δ8.48(t, 1H), 8.40(dd, 1H), 8.30(s, 1H), 8.21(s, 1H), 8.12(d, 1H),8.04(d, 1H), 8.00(m, 2H), 7.85(m, 3H), 7.48(dd, 1H), 7.39(m, 2H),7.04(d, 1H), 3.38(m, 2H), 1.77(m, 2H), 1.08(t, 3H). MS 574.2 m/z (M+H)⁺.

Example 1112-[4-Propylamino-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol)and 3-methyl-4-chlorophenylboronic acid (271 mg, 1.59 mmol) the subtitlecompound was obtained (230 mg, 34%). The product was used directly inthe next step without purification.

b)2-(3-Amino-6-propylaminophenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole(230 mg, 0.48 mmol) and zinc (314 mg, 4.8 mmol) the subtitle compoundwas obtained (187 mg, 100%). MS 392.3 m/z (M+H)⁺.

c)2-[4-Propylamino-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole(94 mg, 0.24 mmol) and 1,2,4-benzenetricarboxylic anhydride (45.6 mg,0.24 mmol) in acetic acid (10 ml) the title compound was obtained (109mg, 81%). ¹H NMR (DMSO) δ 13.79(s, 1H), 8.49(t, 1H), 8.42(dd, 1H),8.31(s, 1H), 8.12(d, 1H), 8.07(m, 2H), 7.83(d, 1H), 7.80(d, 1H),7.71(dd, 1H), 7.61(dd, 1H), 7.48(m, 2H), 7.03(d, 1H), 3.38(m, 2H),2.42(s, 3H), 1.76(m, 2H), 1.08(t, 3H). MS 566.2 m/z (M+H)⁺.

Example 1122-[4-Propylamino-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-propylaminophenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (400 mg, 1.59 mmol)and 4-chlorophenylboronic acid (258 mg, 1.65 mmol) the subtitle compoundwas obtained (284 mg, 64%). MS 408.2 m/z (M+H)⁺.

b) 2-(3-Amino-6-propylaminophenyl)-5-(4-chlorophenyl)benzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(4-chlorophenyl)benzoxazole (284 mg,0.70 mmol) and zinc (455 mg, 7.0 mmol) the subtitle compound wasobtained (264 mg, 99%). The product was used directly in the next stepwithout purification

c)2-[4-Propylamino-5-[5-(4-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-4-chlorophenyl)benzoxazole (136 mg,0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (68 mg, 0.36 mmol)in acetic acid (10 ml) the title compound was obtained (104 mg, 52%). ¹HNMR (DMSO) δ 13.78(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.31(s, 1H),8.12(d, 1H), 8.08(m, 2H), 7.81(m, 3H), 7.71(dd, 1H), 7.54(d, 2H),7.48(dd, 1H), 7.05(d, 1H), 3.35(m, 2H), 1.77(m, 2H), 1.08(t, 3H). MS552.2 m/z (M+H)⁺.

Example 1132-[4-Propylamino-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(3-chloro-4-fluoro)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (360 mg, 0.96 mmol)and 3-chloro-4-fluorophenylboronic acid (250 mg, 1.40 mmol) the subtitlecompound was obtained (408 mg, 99%). MS 426.2 m/z(M+H)⁺.

b)2-(3-Amino-6-propylaminophenyl)-5-(3-chloro-4-fluoro)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole(408 mg, 0.96 mmol) and zinc (627 mg, 9.6 mmol) the subtitle compoundwas obtained (175 mg, 46%). The product was used directly in the nextstep without purification.

c)2-[4-Propylamino-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(3-chloro-4-fluorophenyl)benzoxazole(70 mg, 0.18 mmol) and 1,2,4-benzenetricarboxylic anhydride (34 mg, 0.18mmol) the title compound was obtained (60 mg, 59%). ¹H NMR (DMSO) δ13.78(s, 1H), 8.48(t, 1H), 8.42(dd, 1H), 8.30(s, 1H), 8.11(m, 2H),8.07(d, 1H), 8.01(dd, 1H), 7.83(d, 1H), 7.78(m, 1H), 7.72(dd, 1H),7.50(m, 2H), 7.04(d, 1H), 3.39(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS570.1 m/z (M+H)⁺.

Example 1142-[4-Propylamino-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(3,5-difluoro)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (360 mg, 0.96 mmol)and 3,5-difluorophenylboronic acid (226 mg, 1.40 mmol) the subtitlecompound was obtained (309 mg, 78%). MS 410.2 m/z(M+H)⁺.

b) 2-(3-Amino-6-propylaminophenyl)-5-(3,5-difluoro)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(3,5-difluorophenyl)benzoxazole (309mg, 0.76 mmol) and zinc (497 mg, 7.6 mmol) the subtitle compound wasobtained (227 mg, 79%). The product was used directly in the next stepwithout purification.

c)2-[Propylamino-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(3,5-difluorophenyl)benzoxazole (90mg, 0.24 mmol) and 1,2,4-benzenetricarboxylic anhydride (45 mg, 0.24mmol) the title compound was obtained. (80 mg, 61%). ¹H NMR (DMSO) δ13.77(s, 1H), 8.47(t, 1H), 8.41(dd, 1H), 8.30(s, 1H), 8.20(d, 1H),8.11(d, 1H), 8.07(d, 1H), 7.84(d, 1H), 7.79(dd, 1H), 7.58(m, 2H),7.47(dd, 1H), 7.24(m, 1H), 7.03(d, 1H), 3.38(m, 2H), 1.76(m, 2H),1.08(t, 3H). MS 554.1 m/z (M+H)⁺.

Example 1152-[4-Propylamino-5-[5-(4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-propylaminophenyl)-5-(4-fluoro)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (360 mg, 0.96 mmol)and 4-fluorophenylboronic acid (201 mg, 1.40 mmol) the subtitle compoundwas obtained (184 mg, 49%). MS 392.3 m/z (M+H)⁺.

b) 2-(3-Amino-6-propylaminophenyl)-5-(4-fluoro)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(4-fluorophenyl)benzoxazole (184 mg,0.47 mmol) and zinc (307 mg, 4.7 mmol) the subtitle compound wasobtained (108 mg, 63%). The product was used directly in the next stepwithout purification.

c)2-[4-Propylamino-5-[5-(4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(4-fluorophenyl)benzoxazole (108 mg,0.30 mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.30 mmol)the title compound was obtained. (74 mg, 46%). ¹H NMR (DMSO) δ 13.63(s,1H), 8.49(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.12(d, 1H), 8.08(m, 2H),7.81(m, 3H), 7.68(dd, 1H), 7.47(dd, 1H), 7.32(t, 2H), 7.03(d, 1H),3.34(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 536.2 m/z (M+H)⁺.

Example 1162-[4-Propylamino-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(4-trifluoromethoxy)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (360 mg, 0.96 mmol)and 4-trifluoromethoxyphenylboronic acid (297 mg, 1.40 mmol) thesubtitle compound was obtained (249 mg, 57%). MS 458.3 m/z (M+H)⁺.

b)2-(3-Amino-6-propylaminophenyl)-5-(4-trifluoromethoxy)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(4-trifluoromethoxyphenyl)benzoxazole(249 mg, 0.55 mmol) and zinc (360 mg, 5.5 mmol) the subtitle compoundwas obtained (166 mg, 71%). The product was used directly in the nextstep without purification.

c)2-[4-Propylamino-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(4-trifluoromethoxyphenyl)benzoxazole(83 mg, 0.19 mmol) and 1,2,4-benzenetricarboxylic anhydride (36 mg, 0.19mmol) the title compound was obtained (23 mg, 21%). ¹H NMR (DMSO) δ13.81(s, 1H), 8.49(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.13(m, 2H),8.06(d, 1H), 7.90(d, 2H), 7.84(d, 1H), 7.72(dd, 1H), 7.48(d, 3H),7.04(d, 1H), 3.34(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS 602.1 m/z (M+H)⁺.

Example 1172-[4-Propylamino-5-[5-(4-trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a)2-(3-Nitro-6-propylaminophenyl)-5-(4-trifluoromethyl)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (180 mg, 0.48 mmol)and 4-trifluoromethylphenylboronic acid (137 mg, 0.72 mmol) the subtitlecompound was obtained (126 mg, 59%). MS 442.3 m/z (M+H)⁺.

b)2-(3-Amino-6-propylaminophenyl)-5-(4-trifluoromethyl)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(4-trifluoromethylphenyl)benzoxazole(126 mg, 0.29 mmol) and zinc (189 mg, 2.9 mmol), the subtitle compoundwas obtained (68 mg, 57%). The product was used directly in the nextstep without purification.

c)2-[4-Propylamino-5-[5-(4-trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(4-trifluoromethylphenyl)benzoxazole(116 mg, 0.28 mmol) and 1,2,4-benzenetricarboxylic anhydride (53 mg,0.28 mmol) in acetic acid (10 ml) the title compound was obtained (83mg, 51%). ¹H NMR (DMSO) δ 13.78(s, 1H), 8.49(t, 1H), 8.42(dd, 1H),8.31(s, 1H), 8.13(m, 2H), 8.07(d, 1H), 7.84(m, 2H), 7.74(dd, 2H),7.49(m, 3H), 7.04(d, 1H), 3.37(m, 2H), 1.76(m, 2H), 1.08(t, 3H). MS586.2 m/z (M+H)⁺.

Example 1182-[4-Propylamino-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl-]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid a) 2-(3-Nitro-6-propylaminophenyl)-5-(3-chloro)phenylbenzoxazole

Prepared by the method of Example 15d), from2-(3-nitro-6-propylaminophenyl)-5-bromobenzoxazole (360 mg, 0.96 mmol)and 3-chlorophenylboronic acid (225 mg, 1.40 mmol) the subtitle compoundwas obtained (390 mg, 99%). MS 408.2 m/z(M+H)⁺.

b) 2-(3-Amino-6-propylaminophenyl)-5-(3-chloro)phenylbenzoxazole

Prepared by the method of Example 47b), from2-(3-nitro-6-propylaminophenyl)-5-(3-chlorophenyl)benzoxazole (390 mg,0.96 mmol) and zinc (627 mg, 9.6 mmol) the subtitle compound wasobtained (256 mg, 71%). The product was used directly in the next stepwithout purification.

c)2-[4-Propylamino-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid

Prepared by the method of Example 15f), from2-(3-amino-6-propylaminophenyl)-5-(3-chlorophenyl)benzoxazole (80 mg,0.21 mmol) and 1,2,4-benzenetricarboxylic anhydride (40 mg, 0.21 mmol)in acetic acid (10 ml) the title compound was obtained (42 mg, 37%). ¹HNMR (DMSO) δ 13.82(s, 1H), 8.49(t, 1H), 8.40(dd, 1H), 8.30(s, 1H),8.11(d, 1H), 8.06(m, 2H), 7.81(m, 3H), 7.68(dd, 1H), 7.47(dd, 1H),7.32(m, 2H), 7.04(d, 1H), 3.37(m, 2H), 1.76(m, 2H), 1.07(t, 3H). MS552.1 m/z (M+H)⁺.

Biological Data

Heparanase Assay:

The assay is based upon the specific binding of basic fibroblast growthfactor (bFGF) to heparan sulfate. Hence, heparan sulfate concentrationscan be detected using bFGF and a horse radish peroxidase-conjugated bFGFantibody. Heparan sulfate will ordinarly adhere to plastic well platesurfaces. Following cleavage of high molecular weight heparan sulfate byheparanase, the smaller material generated will no longer adhere to thesurface of a well plate. Thus, upon addition to the plate of bFGF,heparanase activity can be followed as a reduction in bFGF binding.

Nunc Maxisorp 96-well plates are coated for 16 h at room temperaturewith 100 μl/well 0.04 mg/ml heparan sulfate in PBS. The wells are thenaspirated and blocked for 1 h with 200 μl/well 1% BSA-PBS. Followingfive washes with 0.01% BSA, 0.05% Tween20 PBS (wash buffer), 100 μl ofrecombinant human basic FGF (90 ng/ml in 0.1% BSA/PBS) is added per welland the plate is incubated at room temperature for 1 h.

After a further five washes with the wash buffer, 10 μl of test compound(in 10% DMSO) and 90 μl of human heparanase (Vlodavsky I et al., (1999)Nat. Med. 5, 793-802) in 100 mM Sodium acetate, 5 mM CaCl₂, pH 5.5 areadded to each well and the plate incubated for 2 h at 37° C. The humanheparanase used is expressed in insect cells. The wells are washed againwith wash buffer and 100 μl of bFGF antibody-horse radish peroxidaseconjugate is added. The plate is then incubated at room temperature for1 h and subsequently washed five times with wash buffer. 100 μl of TMBperoxidase substrate is added and the colour allowed to develop for 10min. The reaction is stopped with 50 μl 1M H₂SO₄ and the colourintensity is read at 450 nm on a plate reader.

Angiogenesis Assay

A commercial angiogenesis assay for analysing the angiogenic oranti-angiogenic properties of test compounds (AngioKit catalogue no.ZHA-1000, TCS CellWorks Ltd, Buckingham, U.K) was used. In this assay,human endothelial cells were co-cultured with other human cells in aspecifically designed medium. The endothelial cells initially form smallislands within the culture matrix. They subsequently proliferate andthen enter a migratory phase during which they move through the matrixto form threadlike tubule structures. These gradually join up (by 12-14days) to form networks of anatomising tubules which closely resemble acapillary bed structure. These tubules stain positive for vonWillebrand's Factor, Platelet Endothelial Cell Adhesion Molecule-1(PECAM-1 or CD31) and Intercellular Adhesion Molecule-2 (ICAM-2).

The assay is supplied as growing cultures at the earliest stage oftubule formation in a 24 well plate format It is designed so that testcompounds and conditioned media can be added to the cultures withinindividual wells. The resulting effect on tubule formation can then bemonitored. Positive and negative test agents are provided in the kit,e.g. Vascular Endothelial Growth Factor (VEGF) and sumarin. All reagentswere included as part of the kit and the assay was performed accordingto the protocol supplied by TCS CellWorks Ltd. Briefly, on day 1, freshgrowth medium, medium plus control agent or medium plus test compoundwas added to the cells and the cultures were incubated at 37° C., 5%CO₂. Test compounds were dissolved in DMSO and the final concentrationof DMSO in the medium did not exceed 0.1% (v/v). The specified mediumwas changed at days 4, 7 and 9 and the cells were monitored for growth.On day 11, the cells were washed with Dulbecco's Phosphate-BufferedSaline (PBS) and fixed using 70% ethanol (−20° C.) for 30 min at roomtemperature. After fixing, the cells were washed and treated withblocking buffer, 1% BSA in PBS. The cells were stained for PECAM-1 onthe same day, following standard immunohistochemistry procedures wellknown to those skilled in the art, using mouse anti-human CD31 as theprimary antibody and a goat anti-mouse IgG alkaline phosphate conjugate.Tubule formation was quantitatively assessed by measuring PECAM-1positive staining using the image analysis program “Matrox inspector” toevaluate the percentage tubule staining relative to an untreatedcontrol. Inhibition of Heparanase Inhibition of angiogenesis Compound(IC₅₀, μM) (IC₅₀, μM) Example 1 5.0 40.0 Example 2 0.7 5.0 Example 9 3.01.0 Example 15 0.5 1.0 Example 27 0.4 15.0 Example 65 0.8 5.0 Example 660.8 2.0 Example 71 0.5 0.5 Example 92 0.4 0.2 Example 97 0.8 2.0 Example104 0.9 0.75 Example 105 0.2 3.0 Example 108 0.5 2.0 Example 110 0.6 5.0Example 112 0.2 2.0 Example 115 0.5 0.25 Example 116 0.8 0.1

1. A compound of formula (I) or a pharmaceutically acceptable salt orprodrug thereof:

wherein X is O or S; R¹ is a phthalimide carboxylic acid group offormula (II):

R is hydrogen, C₁-C₆ alkyl, aryl or C₁-C₃ alkylaryl; R² is hydrogen,halogen, C₁-C₆ alkyl, OR⁵, a 5-membered heteroaryl ring, or NR⁵R⁵; R³and R⁴ are independently hydrogen, halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂, NR⁷R⁸,NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo, or a 5- to 10-memberedheteroaryl ring which is optionally substituted by C₁-C₆ alkyl; or R³and R⁴ together form a fused phenyl ring or a —O—(CH₂)_(x)—O— group,wherein x is 1 or 2; R⁵ is independently hydrogen, C₃-C₆ alkenyl, C₃-C₆alkynyl, or C₁-C₆ alkyl optionally substituted by hydroxy, C₁-C₃ alkoxy,NR⁷R⁸, phenyl or a 5- or 6-membered heteroaryl ring, wherein phenyl isoptionally substituted by one or more substituents selected fromhalogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo andwherein the heteroaryl ring is optionally substituted by C₁-C₆ alkyl; orR⁵ and R⁵ together with the nitrogen atom to which they are attached,form a 5- or 6-membered ring which optionally contains an additionalheteroatom selected from O, S, and NR¹⁰; R⁶ is C₁-C₆ alkyl, OR⁵, NR⁷R⁸or phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy, CF₃, OCF₃, OR⁵, COR¹⁰, CN, CHO, OCHF₂, NR⁷R⁸, NHCOR⁷, NHSO₂R⁹,S(O)_(p)R⁹ and methylenedioxo; R⁷ and R⁸ are independently hydrogen,phenyl, a 5- to 10-membered heterocyclic ring, C₁-C₆ alkoxy, or C₁-C₆alkyl optionally substituted by phenyl or a 5- to 10-memberedheterocyclic ring, wherein in each case, the phenyl is optionallysubstituted by one or more substituents selected from halogen, CF₃,OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and the heterocyclicring is optionally substituted by C₁-C₆ alkyl; or R⁷ and R⁸ togetherwith the nitrogen to which they are attached form a 5- or 6-memberedheterocyclic ring which is optionally substituted by CONR¹⁰R¹⁰ andoptionally contains an additional heteroatom selected from O, S andNR¹¹; R⁹ is C₁-C₆ alkyl or phenyl optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; R¹⁰ is hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, orC₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃ alkoxy; R¹¹ ishydrogen, phenyl or C₁-C₃ alkyl optionally substituted by phenyl,wherein in each case the phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; and p is 0, 1 or 2; provided that the compound isnot2-[4-(5-carboxy-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phenyl]-6-benzothiazolecarboxylicacid.
 2. A compound according to claim 1 wherein X is O.
 3. A compoundaccording to claim 1 or 2 claim 1 wherein R¹ is meta to the benzoxazoleor benzothiazole group.
 4. A compound according to claim 1 wherein R² ishydrogen, OR⁵ or NR⁵R⁵.
 5. A compound according to claim 1 wherein R³ ishydrogen or halogen.
 6. A compound according to claim 1 wherein R⁴ ishydrogen, halogen, C₁-C₆ alkyl optionally substituted by hydroxy orC₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, phenyl optionally substituted byone or more substituents selected from halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO,OCHF₂ and NR⁷R⁸, or a 5- to 10-membered heteroaryl ring which isoptionally substituted by C₁-C₆ alkyl; or R³ and R⁴ together form afused phenyl ring.
 7. A compound according to claim 6 wherein R⁴ isCOR⁶, phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂ and NR⁷R⁸, or a 5- to10-membered heteroaryl ring which is optionally substituted by C₁-C₆alkyl.
 8. A compound according to claim 1 wherein each R⁵ is,independently, hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆ alkyloptionally substituted by hydroxy, C₁-C₃ alkoxy or a 5- or 6-memberedheteroaryl ring, wherein the heteroaryl ring is optionally substitutedby C₁-C₆ alkyl.
 9. A compound according to claim 1 wherein R⁶ is C₁-C₆alkyl, OR⁵ or NR⁷R⁸.
 10. A compound according to claim 9 wherein R⁶ isOR⁵ or NR⁷R⁸.
 11. A compound according to claim 1 wherein R⁷ and R⁸ areindependently hydrogen, or C₁-C₆ alkyl optionally substituted by phenylor a 5- to 10-membered heterocyclic ring, wherein the phenyl isoptionally substituted by one or more substituents selected fromhalogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and theheterocyclic ring is optionally substituted by C₁-C₆ alkyl; or R⁷ and R⁸together with the nitrogen to which they are attached form a 5- or6-membered heterocyclic ring which is optionally substituted by CONH₂and optionally contains an additional heteroatom selected from O, S andNR¹¹.
 12. A compound according claim 1 wherein R⁹ is C₁-C₆ alkyl.
 13. Acompound which is2-[3-(Benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[3-(Naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[3-(6-Methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[3-(5-Chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[3-(5-Phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-(naphth[2,3-d]oxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-(6-methylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-(5-chlorobenzoxazolyl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Chloro-(5-chlorobenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[4-Chloro-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methyl-5-(5-phenylbenzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methyl-5-(benzoxazol-2-yl)phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(benzofuran-2-yl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-acetyl)phenylbenzoxazol-2yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid; 2-[2-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3,4-dimethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(2-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-[4-(1-hydroxyethyl)]phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-[(5-methyl)thiophen-2-yl]benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-cyano)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-methyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(2,4-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(2,4-dichloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Propargyloxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Ethoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-(2-Methoxyethylamino)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Ethoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-(2-Methoxyethoxy)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Butoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Isopropoxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Allyloxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Hydroxy-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propoxy-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-(3-Furanylmethoxy)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-(2-Methoxyethoxy)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-tetrahydrofuranylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thiophenylmethoxy)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-(4-Morpholinyl)-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid, acetic acid salt;2-[4-Ethylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-(2-Methoxyethylamino)-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Morpholinyl-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Butylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Hexylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Pentylamino-3-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-(3-Benzoxazol-2-yl-4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-(3-Naphtho[2,3-d]oxazol-2-yl-4-propylaminophenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Chlorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(6-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(6-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Bromobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Methoxybenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5,7-Dichlorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Trifluoromethylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Bromo-7-fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Fluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(6,7-Difluorobenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(4-Methylbenzoxazol-2-yl)-4-propylaminophenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-(3-[6-(2-Tetrahydrofuranylmethylaminocarbonyl)benzoxazol-2-yl]phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(4-Piperonylpiperazine-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(4-Piperazinoacetophenone-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(3-Trifluoromethylphenyl)piperazine-1-carbonyl]benzoxazol-2-yl]phenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(3-Carbamoylpiperidine-1-carbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(4-Methoxybenzylaminocarbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-[6-(3,4-Dimethoxybenzylaminocarbonyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid;2-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid methyl ester;2-[3-(5-Carboxy-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-7-carboxylicacid;2-[3-(5-Benzyloxycarbonyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid;2-[3-(5-Methyloxycarbonyl-1,3-dioxo-1,3-dihydroisoindol-2-yl)phenyl]benzoxazole-6-carboxylicacid;2-[5-(5-Bromobenzoxazol-2-yl)-2-methoxyphenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[5-(5-Phenylbenzoxazol-2-yl)-2-(3-thienyl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Fluoro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Chloro-5-(5-phenylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-fluoro-3-formylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(3,4-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-ethylsulfonylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(4-N,N-dimethylaminophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[2-Methoxy-5-[5-(2,3-dichlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(3-chloro-4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(4-trifluoromethylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(3,5-difluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(3-methoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Methoxy-5-[5-(4-methylphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-3-[5-(2-benzofuranyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(3,4-methylenedioxyphenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(2-benzothiophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(3-methyl-4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(4-chlorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(3-chloro-4-fluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(3,5-difluoro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(4-fluorophenyl)benzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(4-trifluoromethoxy)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(4-trifluoromethyl)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid;2-[4-Propylamino-5-[5-(3-chloro)phenylbenzoxazol-2-yl]phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylicacid; or a pharmaceutically acceptable salt or prodrug thereof. 14.(canceled)
 15. A process for the preparation of a compound according toclaim 1 which comprises: a) heating a compound of formula (III):

 wherein R¹ is NH² or a protected derivative thereof with a compound offormula (IV):

 in a suitable acidic medium, or b) heating a compound of formula (III)with a compound of formula (IV) with an organic base in a suitablesolvent, followed by heating in a suitable acidic medium.
 16. Apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt or prodrug thereof:

wherein X is O or S; R¹ is a phthalimide carboxylic acid group offormula (II):

R is hydrogen, C₁-₆ alkyl, aryl or C₁-C₃ alkylaryl; R² is hydrogen,halogen, C₁-C₆ alkyl, OR⁵, a 5-membered heteroaryl ring, or NR⁵R⁵; R³and R⁴ are independently hydrogen, halogen C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₆ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂, NR⁷R⁸,NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo, or a 5- to 10-memberedheteroaryl ring which is optionally substituted by C₁-C₆ alkyl; or R³and R⁴ together form a fused phenyl ring or a —O—(CH₂)_(x)—O— group,wherein x is 1 or 2; R⁵ is independently hydrogen, C₃-C₆ alkenyl, C₃-C₆alkynyl, or C₁-C₆ alkyl optionally substituted by hydroxy, C₁-C₃ alkoxy,NR⁷R⁸, phenyl or a 5- or 6-membered heteroaryl ring, wherein phenyl isoptionally substituted by one or more substituents selected fromhalogen, C₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo andwherein the heteroaryl ring is optionally substituted by C₁-C₆ alkyl; orR⁵ and R⁵, together with the nitrogen atom to which they are attached,form a 5- or 6-membered ring which optionally contains an additionalheteroatom selected from O, S, and NR¹⁰; R⁶ is C₁-C₆ alkyl, OR⁵, NR⁷R⁸or phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy, CF₃, OCF₃, OR⁵ COR¹⁰, CN, CHO, OCHF₂, NR⁷R⁸, NHCOR⁷, NHSO₂R⁹,S(O)_(p)R⁹ and methylenedioxo; R⁷ and R⁸ are independently hydrogen,phenyl, a 5- to 10-membered heterocyclic ring, C₁-C₆ alkoxy, or C₁-C₆alkyl optionally substituted by phenyl or a 5- to 10-memberedheterocyclic ring, wherein in each case, the phenyl is optionallysubstituted by one or more substituents selected from halogen, CF₃,OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and the heterocyclicring is optionally substituted by C₁-C₆ alkyl; or R⁷ and R⁸ togetherwith the nitrogen to which they are attached form a 5- or 6-memberedheterocyclic ring which is optionally substituted by CONR¹⁰R¹⁰ andoptionally contains an additional heteroatom selected from O, S andNR¹¹; R⁹ is C₁-C₆ alkyl or phenyl optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo, R¹⁰is hydrogen, C₃-C₆ alkenyl, C₃-C₆, alkynyl, orC₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃ alkoxy; R¹¹ ishydrogen, phenyl or C₁-C₃ alkyl optionally substituted by phenyl,wherein in each case the phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; and p is 0, 1 or 2, and a pharmaceuticallyacceptable carrier, excipient and/or diluent. 17-22. (canceled)
 23. Amethod for inhibiting heparanase activity in a patient suffering from adisease or disorder in which heparanase activity plays a role,comprising administering to the patient a pharmaceutically effectiveamount of a compound of formula I or a pharmaceutically acceptable saltor prodrug thereof:

wherein X is O or S; R¹ is a phthalimide carboxylic acid group offormula (II):

R is hydrogen, C₁-C₆ alkyl, aryl or C₁-C₃ alkylaryl; R² is hydrogen,halogen, C₁-C₆ alkyl, OR⁵, a 5-membered heteroaryl ring, or NR⁵R⁵; R³and R⁴ are independently hydrogen, halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂, NR⁷R⁸,NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo, or a 5- to 10-memberedheteroaryl ring which is optionally substituted by C₁-C₆ alkyl; or R³and R⁴ together form a fused phenyl ring or a —O—(CH₂)_(x)—O— group,wherein x is 1 or 2; R⁵ is independently hydrogen, C₃-C₆ alkenyl, C₃-C₆alkynyl, or C₁-C₆ alkyl optionally substituted by hydroxy, C₁-C₃ alkoxy,NR⁷R⁸, phenyl or a 5- or 6-membered heteroaryl ring, wherein phenyl isoptionally substituted by one or more substituents selected fromhalogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo andwherein the heteroaryl ring is optionally substituted by C₁-C₆ alkyl; orR⁵ and R⁵, together with the nitrogen atom to which they are attached,form a 5- or 6-membered ring which optionally contains an additionalheteroatom selected from O, S, and NR¹⁰; R⁶ is C₁-C₆ alkyl, OR⁵, NR⁷R⁸or phenyl optionally substituted by one or more substituents selectedfrom halogen, C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy, CF₃, OCF₃, OR⁵, COR¹⁰, CN, CHO, OCHF₂, NR⁷R⁸, NHCOR⁷, NHSO₂R⁹,S(O)_(p)R⁹ and methylenedioxo; R⁷ and R⁸ are independently hydrogen,phenyl, a 5- to 10-membered heterocyclic ring, C₁-C₆ alkoxy, or C₁-C₆alkyl optionally substituted by phenyl or a 5- to 10-memberedheterocyclic ring, wherein in each case, the phenyl is optionallysubstituted by one or more substituents selected from halogen, CF₃,OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and the heterocyclicring is optionally substituted by C₁-C₆ alkyl; or R⁷ and R⁸ togetherwith the nitrogen to which they are attached form a 5- or 6-memberedheterocyclic ring which is optionally substituted by CONR¹⁰R¹⁰ andoptionally contains an additional heteroatom selected from O, S andNR¹¹; R⁹ is C₁-C₆ alkyl or phenyl optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; R¹⁰is hydrogen, C₃-C₆ alkenyl, C₃-C₆ alkynyl, orC₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃ alkoxy; R¹¹ ishydrogen, phenyl or C₁-C₃ alkyl optionally substituted by phenyl,wherein in each case the phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo; and p is 0, 1 or
 2. 24. A method for the treatmentof cancer, angiogenesis, angiogenesis related disorders, inflammatorydiseases, autoimmune disorders, cardiovascular diseases, or renaldisorders comprising administering to a patient suffering from such adisease or disorder a pharmaceutically effective amount of a compound offormula I or a pharmaceutically acceptable salt or prodrug thereof:

wherein X is O or S; R¹ is a phthalimide carboxylic acid group offormula (II):

R is hydrogen, C₁-C₆ alkyl, aryl or C₁-C₃ alkylaryl; R² is hydrogen,halogen, C₁-C₆ alkyl, OR⁵, a 5-membered heteroaryl ring, or NR⁵R⁵; R³and R⁴ are independently hydrogen, halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR¹⁰, COR⁶, NHCOR⁷,NHSO₂R⁹, CN, S(O)_(p)R⁹, phenyl optionally substituted by one or moresubstituents selected from halogen, C₁-C₆ alkyl optionally substitutedby hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR⁶, CN, CHO, OCHF₂, NR⁷R⁸,NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo, or a 5- to 10-memberedheteroaryl ring which is optionally substituted by C₁-C₆ alkyl; or R³and R⁴ together form a fused phenyl ring or a—O—(CH₂)_(—O— group, wherein x is) 1 or 2; R⁵is independently hydrogen,C₃-C₆ alkenyl, C₃-C₆ alkynyl, or C₁-C₆ alkyl optionally substituted byhydroxy, C₁-C₃ alkoxy, NR⁷R⁸, phenyl or a 5- or 6-membered heteroarylring, wherein phenyl is optionally substituted by one or moresubstituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CNand methylenedioxo and wherein the heteroaryl ring is optionallysubstituted by C₁-C₆ alkyl; or R⁵ and R⁵, together with the nitrogenatom to which they are attached, form a 5- or 6-membered ring whichoptionally contains an additional heteroatom selected from O, S, andNR¹⁰; R⁶ is C₁-C₆ alkyl, OR⁵, NR⁷R⁸ or phenyl optionally substituted byone or more substituents selected from halogen, C₁-C₆ alkyl optionallysubstituted by hydroxy or C₁-C₃ alkoxy, CF₃, OCF₃, OR⁵, COR¹⁰, CN, CHO,OCHF₂, NR⁷R⁸, NHCOR⁷, NHSO₂R⁹, S(O)_(p)R⁹ and methylenedioxo; R⁷ and R⁸are independently hydrogen, phenyl, a 5- to 10-membered heterocyclicring, C₁-C₆ alkoxy, or C₁-C₆ alkyl optionally substituted by phenyl or a5- to 10-membered heterocyclic ring, wherein in each case, the phenyl isoptionally substituted by one or more substituents selected fromhalogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰, R¹⁰, CN and methylenedioxo and theheterocyclic ring is optionally substituted by C₁-C₆ alkyl; or R⁷ and R⁸together with the nitrogen to which they are attached form a 5- or6-membered heterocyclic ring which is optionally substituted byCONR¹⁰R¹⁰ and optionally contains an additional heteroatom selected fromO, S and NR¹¹; R⁹ is C₁-C₆ alkyl or phenyl optionally substituted by oneor more substituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰,R¹⁰, CN and methylenedioxo; R¹⁰is hydrogen, C₃-C₆ alkenyl, C₃-C₆alkynyl, or C₁-C₆ alkyl optionally substituted by hydroxy or C₁-C₃alkoxy; R¹¹ is hydrogen, phenyl or C₁-C₃ alkyl optionally substituted byphenyl, wherein in each case the phenyl is optionally substituted by oneor more substituents selected from halogen, CF₃, OCF₃, CHO, OR¹⁰, COR¹⁰,R¹⁰, CN and methylenedioxo; and p is 0, 1 or
 2. 25. The method of claim24 wherein the cancer is melanoma, mesothelioma, lymphoma, leukaemia,fibrosarcoma, rhabdomyosarcoma, mastocytoma, colorectal cancer, prostatecancer, small cell lung cancer, non-small cell lung cancer, breastcancer, pancreatic cancer, kidney cancer, liver cancer, stomach cancer,bladder cancer, skin cancer, uterine cancer, cervical cancer, or ovariancancer.
 26. The method of claim 24 wherein the angiogenesis andangiogenesis related disorders are angiogenesis associated with thegrowth of solid tumors or retinopathy.
 27. The method of claim 24wherein the inflammatory diseases are autoimmune disorders selected fromthe group consisting of rheumatoid arthritis, inflammatory bowel diseaseand multiple sclerosis.
 28. The method of claim 24 wherein thecardiovascular diseases are thromoembolic disease, arterial thrombosisor restenosis.
 29. The method of claim 24 wherein the renal disordersare renal disease associated with diabetes or nocturia.